Dr. Ravi Dhar reviews "IP Barriers in Generic Vaccines in 2014"


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An overview of Intellectual Property Barriers in Generic Vaccines & how to circumvent these. Issues of affordability in tough Patent regime has also been mentioned.

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Dr. Ravi Dhar reviews "IP Barriers in Generic Vaccines in 2014"

  1. 1. IP Barriers in Developing Generic Vaccines & How to Tackle these! (F) Ravi Dhar, Ph.D. (rdhar_in@yahoo.com) (rdhar.birac@nic.in) 5.3.2014 (Mobile: 987-162-0439) Affiliation: BIRAC-DBT, GoI, India Past Affiliations: University of Kashmir, India University of Delhi, India National Institute of Immunology, India Johns Hopkins University, U.S.A. LSU, U.S.A. OTT, Boston University, U.S.A. OTT, NIH, U.S.A. 4/6/2014 1RD_Vaccine Meet_2014 “Protecting the bottom line: Tackling IP barriers in developing generic vaccines”. Vaccine World Summit-2014, Hyderabad, India
  2. 2. 4/6/2014 RD_Vaccine Meet_2014 Acknowledgements IMAPAC_2014, Singapore NIH PubMed Scientific Community across world DBT, GoI NII, India Dr. M.K. Bhan, India Dr. Gerald T. Keusch, BU, USA Dr. Asley Stevens, BU, USA DELCON Library @BIRAC Various Websites USPTO/EPO/IPO Nature Biotechnology & other Journals GHI & OTT, Boston University, USA OTT, NIH, USA 2
  3. 3. 4/6/2014 RD_Vaccine Meet_2014 3 Part-I
  4. 4. 4/6/2014 RD_Vaccine Meet_2014 4 Basic Information: When a new product like drug or vaccine is developed, it is patented. Generic drugs or vaccines can be legally produced as drugs when: 1) the patent has expired, 2) the generic company certifies the brand company's patents are either invalid, unenforceable or will not be infringed, 3) for drugs which have never held patents, or 4) in countries where a patent(s) is/are not in force. The expiration of a patent removes the monopoly of the patent holder on drug sales licensing. Patent lifetime differs from country to country, and typically there is no way to renew a patent after it expires. A new version of the drug/vaccine with significant changes to the compound or structure could be patented, but this requires new clinical trials. In addition, a patent on a changed compound/ or component of vaccine does not prevent sales of the generic versions of the original drug unless regulators take the original drug off the market
  5. 5. 4/6/2014 RD_Vaccine Meet_2014 5 Issue on Generics Patented Medical interventions vs. Requirement of wide range of affordable Medical interventions: Drugs/vaccines/devices/ diagnostics Do we need to produce Generic Products or Modify Intellectual Property Laws & Modify International Treaties
  6. 6. 4/6/2014 RD_Vaccine Meet_2014 6 The first task in developing a utilitarian theory of intellectual property is translating the ideal of the "greatest good of the greatest number” (social welfare in mind), yet allowing the creator to maximize wealth. (Source: Richard Posner, Economic Analysis of Law (3rd ed., Boston: Little, Brown, 1986), pp. 11-15)
  7. 7. 4/6/2014 RD_Vaccine Meet_2014 7 Importance of Generics (U.S. example): In USA 80% of U.S. prescriptions filled with a generic medicine Food and Drug Administration (FDA): This agency must approve every generic medicine before it can be sold in the United States Proving Bio-equivalance 80-85% cost savings by consuming generic medicines $1 Trillion! According to IMS Health, generic medications saved the American health care system $1 trillion between 2002 and 2011 GBR® — Generic Brand Reference Guide This easy-to-use guide—available as a smart phone app or by mail—offers health care professionals cross-referenced lists of brand name and generic medicines.
  8. 8. 4/6/2014 RD_Vaccine Meet_2014 8 “To gain FDA approval, generic medicines must be proven to be “bioequivalent” to their brand name counterparts. That means generic and brand name medicines are the same in the following ways: Active ingredient Maximum amount of medicine in the blood at any given time Total amount of medicine in the blood from the time it’s taken until the body eliminates it Strength and dosage Route of administration—tablet, injection, etc. Expected safety and efficacy FDA evaluation of manufacturing facilities Just because products have the same active ingredient does not mean they are bioequivalent. Once generic bioequivalence is proven, the FDA considers a generic medicine interchangeable with the brand name medicine.” (Source: http://www.mylan.com/products/why-generics)
  9. 9. 4/6/2014 RD_Vaccine Meet_2014 9 Tackling Patent Reforms (US Academia view point-2013) Discourage weak claims of patent infringement brought at least in part for nuisance value Limit the scope of discovery in patent cases prior to the issuance of a claim construction order To contain/address un-necessary litigations. To facilitate the early adjudication of patent infringement suits, we recommend that patentees be required to plead their infringement allegations with greater specificity. To increase transparency and confidence in the market for patent licensing: (a) Government should ask patentees … to disclose and keep up-to-date the identity of parties with an ownership stake or other direct financial interest in their patent rights. (b) Government should consider additional legislation designed to deter fraudulent, misleading, or otherwise abusive patent licensing demands made outside of court. (Source: http://www.patentlyo.com/patent/2013/11/ip-law-professors-rise-up-against-patent-assertion-entities.html)
  10. 10. 4/6/2014 RD_Vaccine Meet_2014 10
  11. 11. An Interesting Article: GLOBAL HEALTH: A NORMATIVE ANALYSIS OF INTELLECTUAL PROPERTY RIGHTS AND GLOBAL DISTRIBUTIVE JUSTICE by Matthew Wayne DeCamp Department of Philosophy Duke University Date: 25 April 2007 (http://dukespace.lib.duke.edu/dspace/bitstream/handle/10161/193/D_DeCamp_Matthew_Wayne_a_052007.pdf?sequence=1) 4/6/2014 11RD_Vaccine Meet_2014
  12. 12. VACCINE TECHNOLOGY TRANSFER: SUMMARY CHART ERAS TECHNOLOGY ECONOMICS POLITICS REGULATION LEGAL AND INTELLECTUAL PROPERTY TECHNOLOGY TRANSFER HEROIC Low Low cost Colonial policy plus altruism Nearly absent Absent Institut Pasteur MID-CENTURY Moving Increasing cost National health programs Strengthening from a low base Absent WHO, national institutes, meetings, education? ERADICATION PROGRAMS Moving Pressure by buyers Altruism, global budget issues Strengthening, WHO prequalification Nearly absent WHO, expert groups, donor funding CURRENT High High cost/low margin, economies of scale Self-sufficiency, biotechnology, donor politics, privatization -Very high domestic and parallel -WHO prequalification Strengthening but mainly on intermediates and processes WHO DCVMN, biotechnology programs, corporate strategic alliances, donors education FUTURE? High Globalization? Access? Financial sustainability? ICH? Research tool issues? Bio-terrorism concerns? Global integration? 12 Source: J.Barton@Stanford, U.S.A. 4/6/2014 RD_Vaccine Meet_2014
  13. 13. 4/6/2014 RD_Vaccine Meet_2014 13 On Generics: (1) A generic drug has lower development costs because it can rely on the research data from the originator product, As far as the generics are concerned, all they have to show is bio-equivalency to the innovators product and piggy-ride on the rest of the innovators data. For challenging molecules, where bioavailability is an issue, the generics have a tough time achieving bio- equivalency, due to several factors, and are a cause for concern. (2) The patent life of a new molecule in the United state is 17 years from first discovery. It takes quite a few years in preclinical, pharmacology, pharmacokinetics,/drug metabolism, toxicology and formulation development, phase 1, 2 and 3 with longest time required in phase 3 depending on the diseases the drug is being targeted for. By this time, in most instances, the time left for return, on about a billion dollars invested to discover and develop a new molecule, is about 10 years or less.
  14. 14. 4/6/2014 RD_Vaccine Meet_2014 14 Part-II
  15. 15. 4/6/2014 RD_Vaccine Meet_2014 15 We need to answer the following critical questions! Q) Whether the current medical innovation system works, and for whom.  Answer: It works & has delivered, however, generics are important & affordable for economically weak sections of society Q) How best could governments balance private commercial interests and public health in their IP laws?  Answer: Difficult question for any developing or under-developed country due to financial constraints. However, to balance these, both are equally important Barrier=Obstruction/ Issue=Important Topic for debate
  16. 16. 4/6/2014 RD_Vaccine Meet_2014 16 Vaccines& Biologics! Vaccine: A preparation of killed microorganisms, living attenuated organisms, or living fully virulent organisms that is administered to produce or artificially increase immunity to a particular disease. (Merriam-Webester.com) Biologic: A preparation, such as a drug, a vaccine, or an antitoxin, that is synthesized from living organisms or their products and used as a diagnostic, preventive, or therapeutic agent. The American Heritage® Medical Dictionary Copyright © 2007, 2004 by Houghton Mifflin Company. Published by Houghton Mifflin Company. All rights reserved. A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from weakened or killed forms of the microbe, its toxins or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as foreign, destroy it, and keep a record of it, so that the immune system can more easily recognize and destroy any of these microorganisms that it later encounters. (Wikipedia)
  17. 17. 4/6/2014 RD_Vaccine Meet_2014 17 Are there Generic Vaccines? There is no (?) such thing as a generic vaccine. Even vaccines based as closely as possible on licensed products must prove safety and efficacy in clinical trials, although for many well-established classes of vaccines, these trials can be smaller than the trials used to license the original vaccine. Vaccines are also biologics, but are generally even more complex than biologic drugs. Source: Expert Rev. Vaccines 8(10): 1439-49.
  18. 18. 4/6/2014 RD_Vaccine Meet_2014 22 Why Generic Vaccines?  Generic vaccines are cheaper  A high percentage of vaccination would drastically decrease the spread of disease  Benefits the Governments by complementing preventive health measures  Employers have to deal with healthy and productive workforce  Families would benefit by gaining workable man-days  Benefits individuals because of good health quality & loss of man days
  19. 19. 4/6/2014 RD_Vaccine Meet_2014 19 Lancet. 2013 Feb 23;381(9867):680-9. doi: 10.1016/S0140-6736(12)62128-X. Epub 2013 Feb 12. Promotion of access to essential medicines for non-communicable diseases: practical implications of the UN political declaration. Hogerzeil HV, Liberman J, Wirtz VJ, Kishore SP, Selvaraj S, Kiddell-Monroe R, Mwangi-Powell FN, von Schoen-Angerer T; Lancet NCD Action Group. Departmentof Global Health, University of Groningen, University Medical Centre, Groningen, Netherlands. h.v.hogerzeil@umcg.nl AAccess to medicines and vaccines to prevent and treat non-communicable diseases (NCDs) is unacceptably low worldwide. In the 2011 UN political declaration on the prevention and control of NCDs, heads of government made several commitments related to access to essential medicines, technologies, and vaccines for such diseases. 30 years of experience with policies for essential medicines and 10 years of scaling up of HIV treatment have provided the knowledge needed to address barriers to long-term effective treatment and prevention of NCDs. More medicines can be acquired within existing budgets with efficient selection, procurement, and use of generic medicines. Furthermore, low-income and middle-income countries need to increase mobilisation of domestic resources to cater for the many patients with NCDs who do not have access to treatment. Existing initiatives for HIV treatment offer useful lessons that can enhance access to pharmaceutical management of NCDs and improve adherence to long-term treatment of chronic illness; policy makers should also address unacceptable inequities in access to controlled opioid analgesics. In addition to off-patent medicines, governments can promote access to new and future on-patent medicinal products through coherent and equitable health and trade policies, particularly those for intellectual property. Frequent conflicts of interest need to be identified and managed, and indicators and targets for access to NCD medicines should be used to monitor progress. Only with these approaches can a difference be made to the lives of hundreds of millions of current and future patients with NCDs. bstract Copyright © 2013 Elsevier Ltd. All rights reserved. PMID: 23410612; [PubMed - indexed for MEDLINE]
  20. 20. 4/6/2014 RD_Vaccine Meet_2014 20 Indian Strength
  21. 21. 4/6/2014 RD_Vaccine Meet_2014 21 Recent Policy of Indian Government The health ministry has revealed that Rs 16,000 crore have been earmarked for distribution of free generic medicines under 12th five year plan through various schemes. "There is an outlay of Rs 16,000 crore for this initiative in the 12th Plan. The initiative is based on the Tamil Nadu model where free medicines procured in bulk by the Tamil Nadu Medical Services Corporation (TNMSC), in generic name, directly from the manufacturers is supplied through an IT enabled supply chain management system to the public” (Indian Health minister-26.8.2013) (http://www.biospectrumindia.com/biospecindia/news/194111/govt-free-generic- medicines-priority#16387c;%20font-size:14px;%20display:block;%20text- decoration:none;%20“)
  22. 22. 4/6/2014 RD_Vaccine Meet_2014 22
  23. 23. 4/6/2014 RD_Vaccine Meet_2014 23 = = Chances of IP generation or Utilization or Circumventing IP
  24. 24. 4/6/2014 RD_Vaccine Meet_2014 24 Vaccine Development The development cycle is quite different from that of traditional pharmaceuticals: Exploratory stage: to understand the disease, its epidemiological data and the right proteins (antigens) to use in preventing or treating the disease; Pre-clinical stage: to assess antigen safety and select the best candidate vaccine; Clinical development: from 10 (Phase I) to 1,000 people (Phase III) are involved in clinical trials and the first batches are produced (clinical batches and industrial batches for compliance); Regulatory approval: all the data collected through the preceding stages are submitted to the relevant health authorities for approval; Manufacturing process: takes up to 22 months to produce a single batch of vaccine; Quality control: approximately 70% of production time is dedicated to quality control.
  25. 25. 4/6/2014 RD_Vaccine Meet_2014 25 CAUTION Once a vaccine is ready, it needs to be preceded by Implementation research (which is an important step toward achieving high vaccine coverage and the uptake of desirable new vaccines) is a highly complex and requires participation of stakeholders from diverse backgrounds to ensure effective planning, execution, interpretation, and adoption of research outcomes. Unlike other scientific disciplines, implementation research is highly contextual and depends on social, cultural, geographic, and economic factors to make the findings useful for local, national, and regional applications.
  26. 26. 4/6/2014 RD_Vaccine Meet_2014 26 Problem Actions required Inadequate preclinical data and lack of detailed information on protective correlates of immunity contribute to product failure in clinical trials Development of more relevant animal models; more human samples to be collected and analysed; increased use of experimental human challenge infections Lack of information on the infectious exposures of intended vaccine recipients More human samples to be collected and analysed Vaccines are to be used in populations with less- responsive immune systems Gain a greater understanding of the mechanisms of action of currently used adjuvants; development of vaccine delivery systems specifically for use in immunocompromised populations Antigenic variation requires constant updating of vaccine formulations Seek conserved antigens; monitor genetic variation of infectious organisms in the community High costs of vaccine development result in premature abandonment of potentially useful products More investment in vaccine research Inadequate access to vaccines in poorer countries, especially those for use against tropical diseases More tiered pricing strategies; facilitate the development of vaccines in developing countries The current challenges for vaccine development J Med Microbiol July 2012 vol. 61 no. Pt 7 889-894
  27. 27. 4/6/2014 RD_Vaccine Meet_2014 27 Part-III
  28. 28. 4/6/2014 RD_Vaccine Meet_2014 28 The Contradiction in IP protection “An R&D system exclusively based on IP does not generate sufficient economic incentives for pharmaceutical companies to develop medicines needed predominantly in poor countries. In fact, many pharmaceutical companies have downsized or shut down their infectious-disease R&D divisions, the recent one being Astra Zeneca closure in india. IP often by itself, acts as a barrier to innovation : ‘Patent thickets’severely limit the ability of researchers to develop new treatments and technologies. Increasingly, the existing approach to R&D is failing rich countries too, with few pharmaceutical companies successfully replenishing their drug pipelines”
  29. 29. 4/6/2014 RD_Vaccine Meet_2014 29 Possible Solution (Israeli experience) Takeda (10th largest pharma company in the world), advances a very strong late-stage pipeline to develop a successful vaccine business that has the potential to be commercially attractive while at the same time creating low-cost health solutions (i.e. vaccines) for some of the poorest countries in the world (i.e. emerging markets). In order to do so, the company is building its strong vaccine franchise network to achieve this goal.
  30. 30. 4/6/2014 RD_Vaccine Meet_2014 30 Recommendation of Sixty-fifth (65th) WHA, 194 Member States endorsed the GVAP's goals and the following six strategic objectives (May 2012): (1) All countries commit to immunization as a priority for all stakeholders in a country, and establish good governance for effective, high-quality immunization services. (2) Individuals and communities should demand immunization as both their right and responsibility. (3) Equitable access to immunization should be a core component of the Right to Health. (4) Strong immunization systems should become integral parts of well-functioning health systems so that it works in a coordinated manner to achieve national-level goals. (5) Immunization programs should have sustainable and appropriate level of funding, management, and oversight to ensure the sustainability of immunization programs. (6) A continuous improvement and innovation in research and development is necessary in all aspects of immunization, from communication to genomics at country, regional, and global research levels to maximize the benefits of immunization (Source :Alonso, P.L., deQudros C.A., Robert M. & Lal A.A. (2013) Editorial in Vaccine 31(2), April 2013)
  31. 31. 4/6/2014 RD_Vaccine Meet_2014 31 Generic vaccines are highly regulated!  Being biological products, Governments are concerned about regulating all aspects of vaccine development namely:- Product safety Clinical trials Pricing Reimbursement Patent protection R&D incentives  Mode of administration Issues of thermo-stability managed by generic manufacturers Concept of differential pricing
  32. 32. 4/6/2014 RD_Vaccine Meet_2014 32 Global Support for Vaccine Development
  33. 33. 4/6/2014 RD_Vaccine Meet_2014 33 Part-IV
  34. 34. 4/6/2014 RD_Vaccine Meet_2014 34 IP Barriers for Vaccine Development Technical Legal Regulatory Ethical Societal
  35. 35. 4/6/2014 RD_Vaccine Meet_2014 35 IP Barriers Technical The term “Technology Barrier” refers to the use of laws, directives, regulations and standards to regulate trade between countries. Utilizing certification, inspection and such process to impose new requirements on import goods based on technology, health concern, packaging and labelling. On the surface, it is to raise the quality standard of the merchandize, but the ultimate is to limit import. In this tariff verses non-tariff era, the standards set for technology barriers are said to protect the welfare of the consumer and thus favoured by all countries. Since it improves the quality and protects consumer rights, it is therefore, accepted and implemented in different countries Legal Regulation According to “article 20?(general exception) and “article 21?(safety exception) of GATT, nations have the right to protect the safety of its people and its plants. When safety is threatened, they can take exceptions from GATT in setting technical standards. This is outside the rules that regulate import quota base on the national per capita income rule. However, as mentioned, technical standards are usually wrongfully used in international trade for self-protection. It has become means to limit import. It has become barriers to free trade. The Ecuador resolution results in the TBT treaty, , hereon referred as SPS Treaty. Besides the treaty, there are also other conditions that constituted WTO’s restriction on utilizing technology barrier on international trade. Ethical Societal: depends on economic status, poverty, affordability etc??
  36. 36. IP issues Virus genes, gene sequences, treatments, and vaccines: These include proprietary claims on viruses originating in developing countries and that were shared with the international community for public health purposes (H5N1 Vaccines) Synthetic consensus Antigens: The patent includes claims that cover the synthetic consensus H1 antigen and DNA constructs and vaccines that include this antigen, including universal influenza vaccine INO-3510. This patent also covers methods of treating a patient using the SynCon® universal influenza vaccine (http://www.news-medical.net/news/20120326/USPTO-issues-patent-to-Inovios-SynCon-H1N1- influenza-vaccine.aspx) Vaccine Stabilization Technology: The novel technology could eliminate the need for cold-chain production, transportation and storage for Alum adjuvanted vaccines. ThermoVax is exclusively licensed to Soligenix by the University of Colorado. The main patent claims describe methods to prepare an immunologically-active adjuvant-bound, freeze-dried, thermostable vaccine composition in which the vaccine uses Alum adjuvants. The main patent also includes claims for the adjuvant-bound composition itself. 4/6/2014 36RD_Vaccine Meet_2014
  37. 37. 4/6/2014 RD_Vaccine Meet_2014 37 IP Barriers Technical The term “Technology Barrier” refers to the use of laws, directives, regulations and standards to regulate trade between countries. Utilizing certification, inspection and such process to impose new requirements on import goods based on technology, health concern, packaging and labelling. On the surface, it is to raise the quality standard of the merchandize, but the ultimate is to limit import. In this tariff verses non-tariff era, the standards set for technology barriers are said to protect the welfare of the consumer and thus favoured by all countries. Since it improves the quality and protects consumer rights, it is therefore, accepted and implemented in different countries
  38. 38. 4/6/2014 RD_Vaccine Meet_2014 38 IP Barriers Legal Infringements of various scales – has become a subsidiary business for some
  39. 39. 4/6/2014 RD_Vaccine Meet_2014 39 IP Barriers Regulation According to “article 20?(general exception) and “article 21?(safety exception) of GATT, nations have the right to protect the safety of its people and its plants. When safety is threatened, they can take exceptions from GATT in setting technical standards. This is outside the rules that regulate import quota base on the national per capita income rule. However, as mentioned, technical standards are usually wrongfully used in international trade for self-protection. It has become means to limit import. It has become barriers to free trade. The Ecuador resolution results in the TBT treaty, , hereon referred as SPS Treaty. Besides the treaty, there are also other conditions that constituted WTO’s restriction on utilizing technology barrier on international trade.
  40. 40. 4/6/2014 RD_Vaccine Meet_2014 40 IP Barriers Ethical READ this: http://www.allergysa.org/journals/2009/november/vaccination-and-ethical-issues.pdf ???? “Compulsory vaccination was originally introduced for smallpox, and mandatory immunisation is still in force in some countries. Vaccination is no longer compulsory in South Africa, but carries significant benefits both for individuals and for the community. An ethical dilemma is posed by the fact that the vaccine is administered to a healthy child, with the intention of protecting both the individual child and the community, but the risk has to be borne by the child alone. The anti-vaccination lobby claims that there is an association between measles-mumps-rubella (MMR) vaccine and autism, but there are no data to support this. Parents generally have the best interests of the child at heart, and parental autonomy to refuse vaccination should be respected unless the child is considered to be at significant risk from that refusal. Equity of access to vaccinations is ensured by the public health system in South Africa. The introduction of pneumococcal conjugate vaccine and rotavirus vaccine into the immunisation programme is in the interests of the public, but carries significant cost implications.”
  41. 41. 4/6/2014 RD_Vaccine Meet_2014 41 IP Barriers Societal: depends on unmet medical needs, economic status, poverty, affordability etc??
  42. 42. 4/6/2014 RD_Vaccine Meet_2014 42 Inspite of all the issues, people need generic vaccines even in developed countries. This has become more important due to increase in poverty levels world wide
  43. 43. 4/6/2014 RD_Vaccine Meet_2014 43 R&D spending has a direct relationship with development of new essential products
  44. 44. 4/6/2014 RD_Vaccine Meet_2014 44
  45. 45. 4/6/2014 RD_Vaccine Meet_2014 45 Part-V
  46. 46. 4/6/2014 RD_Vaccine Meet_2014 46 Multiple Layers of IP Protection in Vaccine Development
  47. 47. 4/6/2014 RD_Vaccine Meet_2014 47 Platform Processes DNA Sequences Cell Lines Antigen Bio-processing/ Production Expression of Cells used Vehicle Immunostim Formulations & Excipients Animal Models Issues related to New Clinical Trials Delivery Device Yield improvement Know-how & Trade Secrets Fishing out new IP Mechatronics used for vaccine production Reference Reagents Protocols Adjuvant VACCINES (Source: http://www.wto.org/english/tratop_e/trips_e/techsymp_feb11_e/friede_18.2.11_e.pdf ) (modified)
  48. 48. 4/6/2014 RD_Vaccine Meet_2014 48 Do True Generic Drugs Exist? True 'generic' vaccines do not exist Complex biological drugs: equivalence can not be demonstrated by simple tests. Full clinical safety and efficacy (or surrogate) testing of 'copy' required. Even in absence of patent barriers numerous barriers to vaccine production – Expertise, know how, previous clinical data – Cost (investment, production) – Clinical studies (possibly very large if comparing efficacy to existing vaccine) http://www.who.int/phi/news/Presentation15.pdf
  49. 49. 4/6/2014 RD_Vaccine Meet_2014 49 Trade secrets/know-how Many critical aspects of the operations of bio- processing facilities are valuable knowledge. In some jurisdictions, this knowledge can be protected under trade secret law. It is customary for any pharmaceutical production plant to keep its standard operating procedures as trade secrets, given the considerable time and resources involved in fine tuning operations. SOPs & Business Plans are also restricted By extension, employees of such plants will need to be informed of procedures for keeping information confidential and should have related clauses in their employment contracts. Misappropriation: Merck vs SKB 1999
  50. 50. 4/6/2014 RD_Vaccine Meet_2014 50 Vaccines under development in India in academic institutions Human vaccines under development Institutions involved Status Cholera vaccine Dengue vaccine Hepatitis A HIV vaccine Japanese encephalitis vaccine Leishmania vaccine Malaria vaccine Rotavirus vaccine Tuberculosis vaccine Typhoid vaccine IMTECH, Chandigarh; NICED, Kolkata ICGEB, N. Delhi NIV, Pune THSTI, Gurgaon; IAVI NII, N. Delhi NIV and University of Pune, Pune IOP and IMM, N. Delhi ICGEB, N. Delhi AIIMS, New Delhi; CDC and NIH, USA THSTI and UDSC, N. Delhi AIIMS, N. Delhi Live oral cholera vaccine candidate vaccine strain VA1.4 Phase II studies completed, Phase III will begin soon. Efforts on developing safe, efficacious and inexpensive tetravalent dengue vaccine candidate are underway. An agreement for transfer has been signed with BBIL for further development. Efforts are underway to design of candidate vaccines to elicit neutralizing antibodies against HIV. (1) Vero cell-derived inactivated JEV vaccine developed was transferred to Panacea Biotech. (2) JE chimeric peptide based vaccine has been transferred BBIL, Hyderabad. Use of live-attenuated Leishmania donovani parasites as vaccine candidates against visceral leishmaniasis is being tested at laboratory scale. PvDBPII for P. vivax and JAIVAC-1 vaccine for P. falciparum has been transferred to BBIL, Hyderabad. Phase I clinical trials completed. Phase III clinical trial of rotavirus vaccine 116E underway at three sites: SAS, N. Delhi; CMC, Vellore; KEM Hospital Pune. Recombinant BCG 85c (rBCG85c), one of several candidates that showed promising results in animals, is being developed as a TB vaccine. A Vi-conjugate typhoid vaccine technology has been transferred to USV Ltd. Mumbai. AIIMS, All India Institute of Medical Sciences; BBIL, Bharat Biotech International Ltd.; CDC, US Centers for Disease Control and Protection; HIV, Human immunodeficiency virus; IAVI, International AIDS Vaccine Initiative; ICGEB, International Center for Genetic Engineering and Biotechnology; IMM, Institute of Molecular Medicine; IMTECH, Institute of Microbial Technology; IOP, Institute of Pathology; JEV, Japanese encephalitis virus; NICED, National Institute of Cholera and Infectious Diseases NII, National Institute of Immunology; NIH, US National Institutes of Health; NIV, National Institute of Virology; THSTI, Translational Health Science Technology Institute; UDSC, University of Delhi, South Campus. a Compiled from Annual reports of Department of Biotechnology and Indian Council of Medical Research. Source: Sen Gupta, Sanjukta, et al. (2013) Vaccine development and deployment: Opportunities and challenges in India. Vaccine 31(2), B43-B53
  51. 51. 4/6/2014 RD_Vaccine Meet_2014 51 Bolar Provision/Research Exemption Implemented from 2003 in India Useful for Indian generic manufacturers Technical consultations should be carried out to examine the possibility of any alteration in vaccine formulation (e.g. vaccines with or without preservative, with or without adjuvant, liquid or lyophilized etc.) that could enable the use of a vaccine in the existing schedule. Such a consultative process should include scientists, program managers, cold chain managers and representatives of the manufacturers. The combinations vaccines have shown to improve coverage, and reduce non-program costs, especially in countries with similar issues. These factors should be considered before making a decision on the use of combination vaccines Source: National Vaccine Policy, India, 2011
  52. 52. 4/6/2014 RD_Vaccine Meet_2014 52 Drug Applications and Current Good Manufacturing Practice (cGMP) Regulations (US-FDA) FDA ensures the quality of drug products by carefully monitoring drug manufacturers' compliance with its Current Good Manufacturing Practice (CGMP) regulations. The CGMP regulations for drugs contain minimum requirements for the methods, facilities, and controls used in manufacturing, processing, and packing of a drug product. The regulations make sure that a product is safe for use, and that it has the ingredients and strength it claims to have. The approval process for new drug and generic drug marketing applications includes a review of the manufacturer's compliance with the cGMP.
  53. 53. 4/6/2014 RD_Vaccine Meet_2014 53 Need for Effective databases Lack of patent claim information in publicly available Indian patent databases hampers pace of R&D. Bharat Biotech’s R&D was delayed due to uncertainty about the status of patent protection for HPV antigens in India. Moreover, many countries in Africa, Latin America and Southeast Asia – potential markets for HPV vaccines – lack online patent databases, making it very difficult to determine which LMCs have pending or granted patents. More importantly, LMC companies generally lack the substantial financial and human resources necessary to perform freedom to operate (FTO) analyses using proprietary databases available in developed countries. IPO database needs to be more robust?? Source: Serum Institute of India & Bharat Biotech
  54. 54. 4/6/2014 RD_Vaccine Meet_2014 54 Padmanabhan S. et al. (2010) Intellectual Property, Technology Transfer and Developing Country Manufacture of Low-cost HPV vaccines - A Case Study of India. Nat Biotechnol. 2010 July; 28(7): 671–678. doi: 10.1038/nbt0710-671 , PMCID: PMC3138722, NIHMSID: NIHMS270118 MoHFW - http://mohfw.nic.in/WriteReadData/l892s/1084811197NATIONAL%20VACCI NE%20POLICY%20BOOK.pdf
  55. 55. 4/6/2014 RD_Vaccine Meet_2014 55 Circumventing Patent Laws for affordable Vaccines Credits: S. Padmanabhan, Nature Biotechnology, 2010
  56. 56. 4/6/2014 RD_Vaccine Meet_2014 56 http://mohfw.nic.in/WriteReadData/l892s/1084811197NATIONAL%20VACCINE%20POLICY%20BOOK.pdf MoHFW, GoI Improving the institutional capacity for intellectual property (IP) management and technology transfer will help investigators involved in the research to understand the patent claims and will enable them to make sound judgments, during the product development. There are a few steps needed in this arena: • Strengthening Indian patent office, reducing the time to examine and grant a patent, and creation of more comprehensive IP databases in India • Encouraging technology transfer from multinational companies to develop products and gaining access to technologies and know-how • Indian patent law may have provisions to permit compulsory licensing in special situations like the H1N1 pandemic or in situations, where a technology/intermediate is needed for vaccine development. • The country should develop/use expertise to study the flexibilities enshrined in the Trade Related Aspects of Intellectual Property rights (TRIPS) agreement to reduce the negative impact of the patents. The arrangements like ‘Bolar provision’ which permits the manufacturers of generic pharmaceuticals to begin product development, while the patent is still in force. This could be particularly helpful in reducing the lead-time to obtain regulatory clearances during vaccine development. • Collective management of IPR and open access agreements should be resorted to improve innovation and access. Innovations in ways to deal with IPR of new vaccines need to emerge through innovative funding of R&D. • It is suggested that a body is created to acquire and hold IPR for technologies beneficial for use in public health. This body could then license the technology to emerging manufacturers on acceptable terms for development of vaccines and related products.
  57. 57. 4/6/2014 RD_Vaccine Meet_2014 57 Local R&D Effort: Success Stories: Rotavirus Vaccine (2013) •India’s new rotavirus vaccine, promises to drastically reduce diarrhoeal deaths •Rotavac can be safely administered along with oral polio drops •When licensed, Rotavac will be available at a dollar-per-dose and compares well with existing vaccines
  58. 58. IP Coverage on Vaccine Patents Vaccine Methods of prophylaxis and treatment Modified de-activated organism DNA, amino acid sequence of antigens, modifications, fusion proteins Expression systems Adjuvants Formulations, dosage, carriers, excipients, diluents etc. Delivery device and dosing regimen Research tools and platform technologies Processes – conjugation technology, expression systems, manufacturing and purification processes 4/6/2014 58RD_Vaccine Meet_2014
  59. 59. What are the Implications? What is being patented? Where are they patented? What obstacles does patent protection present for the development and production of vaccines? How can one legally manufacture and import/ export vaccines? What is the timeline for IPR protection on the technologies? What obstacles does patent protection present for rapid dissemination of vaccines in time of public health need/crisis? Claim overlap periods Claim 1 Claim 7 Claim 10 Claim 11 4/6/2014 59RD_Vaccine Meet_2014
  60. 60. 4/6/2014 RD_Vaccine Meet_2014 60 IP Issues Related to Antigens •First-generation cervical cancer vaccines "do not seriously inhibit" the efforts of developing country vaccine manufacturers (DCVMs) to develop these vaccines •The current vaccines do not protect against several cancer-causing strains of HPV that present in low-income countries, and suggest that DCVMs could make products that include antigens missing in the patented versions
  61. 61. 4/6/2014 RD_Vaccine Meet_2014 61 Issues related to DNA sequences Poorly designed analysis (H5N1 case): “There are many techniques for filing invention disclosures that render the searchability of DNA or protein sequences very difficult” & “ finding DNA or protein sequences disclosed in or claimed In patents is extraordinarily difficult”. Claims on less variable “conserved” parts of genome Follow one system of classification while doing FTOs or searches  Non-disclosure of sequences in less known but potent organisms (Source: TWN-2011)
  62. 62. (http://www.ipaustralia.gov.au/get-the-right-ip/patents/about-patents/what-can-be-patented/patents-for-biological-inventions/) Patents for Expression Vectors & biological inventions A standard patent can be obtained for isloated bacteria, cell lines, hybridomas, related biological materials and their use, and genetically manipulated organisms. Examples of patentable inventions include: isolated bacteria and other prokaryotes, fungi (including yeast), algae, protozoa, plasmids, viruses, prions cell lines, cell organelles, hybridomas genetic vectors and expression systems apparatus or processes for enzymology or microbiology compositions of micro-organisms or enzymes propagating, preserving or maintaining micro-organisms mutagenesis or genetic engineering fermentation or enzyme using processes to synthesise a desired compound or composition measuring or testing processes involving enzymes or micro-organisms processes using enzymes or micro-organisms to liberate, separate, purify or clean the use of micro-organisms to produce food or beverages. 4/6/2014 62RD_Vaccine Meet_2014
  63. 63. 4/6/2014 RD_Vaccine Meet_2014 63 Genetic inventions and their patent claims (A) For genetic inventions, many different types of patent can be found. They vary as to the kinds of claims used and how the set of claims is structured. There are at least three common categories of patent in this field. DNA coding for industrially useful expression products. The cloning of a DNA coding sequence can enable the commercial production of an important therapeutic protein, such as a blood protein or a vaccine. Such an achievement can represent a clear advance in pharmaceutical technology and deserve legal protection, provided the innovation meets standard criteria of patentability. Similarly, the cloning of DNA coding sequences which leads to advances in plant biotechnology, thereby improving agricultural Products like plant derived vaccines, practices and productivity, is patentable. A typical claims structure in such a therapeutic product patent will cover the following: 1. DNA of specific function and/or nucleotide sequence. 2. A recombinant vector (plasmid) containing DNA of (1). 3. A genetically modified organism containing DNA of (1). 4. A method of production of polypeptide expressed by DNA of (1). 5. The expressed polypeptide per se (only if novel, i.e. differing in some respect from the naturally occurring protein).
  64. 64. Patents for genetic modification or manipulation A standard patent can also be obtained for inventions involving: genotypically or phenotypically modified living organisms, for example, genetically modified bacteria, plants and non-human organisms (patenting of plant varieties is described in Plant Breeder's Rights) isolated DNA, RNA, chromosomes and genes (including human DNA and genes) isolated products of such DNA, RNA and genes including polypeptides and proteins. Examples of patentable inventions include: synthetic genes or DNA sequences mutant forms and fragments of gene sequences an isolated DNA coding sequence for a gene an isolated protein expressed by a gene vectors (such as plasmids or bacteriophage vectors or viruses) containing a transgene methods of transformation using a gene host cells carrying a transgene higher plants or animals carrying a transgene organisms for expression of a protein from a transgene general recombinant DNA methods such as PCR and expression systems 4/6/2014 64RD_Vaccine Meet_2014
  65. 65. Patents for DNA or gene sequences Human beings and the biological processes for their generation are not patentable. Although standard patents can be obtained for biological material such as micro-organisms, nucleic acids, peptides and organelles, this material is only patentable if it has been isolated from its natural environment, or has been synthetically or produced by recombinant mode, e.g., DNA or genes in the human body are not patentable. A DNA or gene sequence that has been isolated may be patentable. Patent specifications must also describe a specific use for a biological material. For example, if the invention relates to a gene, the specification must disclose a specific use for the gene, such as its use in the diagnosis or treatment of a specific disease, or its use in a specific enzymatic reaction or industrial process. 4/6/2014 65RD_Vaccine Meet_2014
  66. 66. 4/6/2014 RD_Vaccine Meet_2014 66 Examples of genetic inventions and their patent claims (B) It should be noted that these different forms of claims may not all be present in a single patent; official patent regulations in certain countries may require them to be divided into two or more separate patent applications. The US patents on breast cancer genes (BRCA1 and BRCA2) and their use in diagnostic testing are illustrative examples of this practice. Genes which control biological pathways. Research continues to identify receptors and genes involved in biological pathways. When such a gene is located, it may be possible to correlate a malfunction in the pathway with a mutation or loss of this gene. The cDNA and the encoded polypeptide would be considered targets for diagnosis and drug discovery or vaccine development. One type of invention in this category would be the use of the target to discover substances which achieve some useful effect by binding to the target. This would also include substances which, by blocking the target, prevent entry of pathogens such as viruses into the cell. Typical claims are: 1. The receptor peptide or polypeptide (protein) of a defined sequence. 2. DNA coding for the receptor (1). 3. A transformed cell expressing the receptor (1). 4. An assay system comprising the transformed cell (3). 5. A method of identifying an agonist or antagonist of the receptor. 6. Agonists or antagonists of receptor (1) identified by method (5), (a claim of this type is allowed with great difficulty).
  67. 67. 4/6/2014 67RD_Vaccine Meet_2014 Why China is a genetic powerhouse with a problem - The Globe and ... www.theglobeandmail.com Dec 15, 2012 - But not just human DNA. Once known as the Beijing Genomics Institute, BGI is on a mission to sequence the genomes of a vast array of living……. In the South China city of Shenzhen, a thriving manufacturing hub known for cheap goods and high-tech electronics, the genetic secrets of life roll off machines by the minute. Here at the global headquarters of BGI-Shenzhen, housed in a former shoe factory, the genomic revolution runs on an industrial scale. Powered by an army of young lab technicians and banks of high-end, U.S.-made sequencers that hum 24/7, the DNA of human kind is decoded with conveyor-belt speed and brute force
  68. 68. 4/6/2014 RD_Vaccine Meet_2014 68 Recent Pat Drug Deliv Formul. 2008;2(1):68-82 Potential of nanocarriers in genetic immunization. Khatri K, Goyal AK, Vyas SP. Source Drug Delivery Research Laboratory, Department of Pharmaceutical Sciences, Dr. H. S. Gour Vishwavidyalaya, Sagar, MP 470003, India. Abstract DNA vaccination (or genetic immunization) strategies provide important opportunities for improving immunization, since both humoral and cell- mediated responses are induced. The use of genetic vaccines for inducing immunity to infectious agents can eliminate or significantly alleviate the pathology associated with a broad range of infections. A requirement for efficient DNA vaccination is the development of gene delivery systems capable of overcoming barriers to gene transfection. Compared to viral systems, nonviral systems are considered to be safe, cheap, multiple delivery is possible and able to deliver larger pieces of DNA. Also, these nanocarriers avoid DNA degradation and facilitate targeted delivery to antigen presenting cells. This review describes the potential of non-viral nanocarrier construct(s) in genetic immunization. Issued patents in the field were retrieved from the US patent database. Various carrier systems used to deliver plasmid DNA were reviewed in detail. PMID:19075899 [PubMed - indexed for MEDLINE]
  69. 69. 4/6/2014 RD_Vaccine Meet_2014 69 Case History: IP Issues in Influenza Vaccines  Further IP Considerations: Reverse Genetics Patents and WHO GISN H5N1 Vaccine Seed Strains  Antisera Research: Emerging Intellectual Property Claims  Conflicting Priorities: Public Research and Private Patents, Two ????
  70. 70. Platform processes Very useful Generate huge IP 4/6/2014 70RD_Vaccine Meet_2014
  71. 71. 4/6/2014 RD_Vaccine Meet_2014 71
  72. 72. 4/6/2014 RD_Vaccine Meet_2014 72 1 7,223,411 Herpesvirus replication defective mutants 2 7,186,559 Apparatus and method for electroporation of biological samples 3 7,141,425 Apparatus and method for electroporation of biological samples 4 7,141,408 Plasmid maintenance system for antigen delivery 5 7,138,112 Plasmid maintenance system for antigen delivery 6 7,125,720 Plasmid maintenance system for antigen delivery 7 7,115,269 Attenuated Salmonella strain used as a vehicle for oral immunization 8 7,078,218 Alphavirus particles and methods for preparation 9 7,045,335 Alphavirus replicon vector systems 10 7,029,916 Apparatus and method for flow electroporation of biological samples 11 7,026,155 Method of reducing bacterial proliferation 12 6,995,008 Coordinate in vivo gene expression Delivery Systems
  73. 73. 4/6/2014 RD_Vaccine Meet_2014 73 Bio-manufacturing of Vaccines PAT. NO Title 1 8,440,791 Thimerosal removal device 2 8,388,955 Fc variants 3 8,367,805 Fc variants with altered binding to FcRn 4 8,338,574 FC variants with altered binding to FCRN 5 8,324,351 Fc variants with altered binding to FcRn 6 8,318,907 Fc variants with altered binding to FcRn 7 8,101,720 Immunoglobulin insertions, deletions and substitutions 8 8,093,357 Optimized Fc variants and methods for their generation 9 8,034,335 High-titer retroviral packaging cells 10 8,030,071 Restoration of cholesterol independence and its use as a selectable marker in NS0 cell culture 11 7,964,403 Preparation of vaccine master cell lines using recombinant plant suspension cultures 12 7,901,921 Viral purification methods 13 7,879,338 Vectors and methods for immunization against norovirus using transgenic plants 14 7,553,666 Preparation of vaccine master cell lines using recombinant plant suspension cultures 15 6,395,538 Method and system for providing real-time, in situ biomanufacturing process monitoring and control in response to IR spectroscopy 16 6,266,569 Method and system of computing similar to a turing machine
  74. 74. 4/6/2014 RD_Vaccine Meet_2014 74 1 8,168,421 Microbial vaccine and vaccine vector 2 7,704,491 Recombinant human metapneumovirus and its use 3 7,169,396 Reference clones and sequences for non-subtype B isolates of human immunodeficiency virus type 1 4 6,897,301 Reference clones and sequences for non-subtype B isolates of human immunodeficiency virus type 1 5 6,492,110 Reference clones and sequences for non-subtype B isolates of human immunodeficiency virus type 1 6 6,310,045 Compositions and methods for cancer immunotherapy 7 5,662,896 Compositions and methods for cancer immunotherapy Reference Reagents
  75. 75. 4/6/2014 RD_Vaccine Meet_2014 75 1 8,507,658 Ex vivo animal or challenge model as method to measure protective immunity directed against parasites and vaccines shown to be protective in the method 2 8,507,445 Compositions and methods of use of targeting peptides for diagnosis and therapy of human cancer 3 8,507,206 Monoclonal antibodies that target pathological assemblies of amyloid .beta. (Abeta) 4 8,506,969 Efficient cell culture system for hepatitis C virus genotype 7a 5 8,501,194 Vaccine for viruses that cause persistent or latent infections 6 8,498,879 Automated systems and methods for obtaining, storing, processing and utilizing immunologic information of individuals and populations for various uses 7 8,497,351 Nucleic acid and corresponding protein entitled 162P1E6 useful in treatment and detection of cancer 8 8,497,292 Translational dysfunction based therapeutics 9 8,491,909 Methods and compositions for dosing of allergens 10 8,486,421 Antigen-norovirus P-domain monomers and dimers, antigen- norovirus P-particle molecules, and methods for their making and use 11 8,486,413 Immunological compositions as cancer therapeutics Animal models for Vaccines
  76. 76. 4/6/2014 RD_Vaccine Meet_2014 76 Carriers for Vaccines United States Patent # 8,506,968; Inventor: Akeefe, et al.; Eli Lilly and Company (Indianapolis, IN); Filed December 28, 2009, Date of Grant: August 13, 2013 SARS vaccine compositions and methods of making and using them Abstract Described is a composition and method for reducing the occurrence and severity of infectious diseases, especially infectious diseases such as SARS, in which lipid- containing infectious viral organisms are found in biological fluids, such as blood. The present invention employs solvents useful for extracting lipids from the lipid- containing infectious viral organism thereby creating immunogenic modified, partially delipidated viral particles with reduced infectivity. The present invention provides delipidated viral vaccine compositions, such as therapeutic vaccine compositions, comprising these modified, partially delipidated viral particles with reduced infectivity, optionally combined with a pharmaceutically acceptable carrier or an immunostimulant. The vaccine composition is administered to a patient to provide protection against the lipid-containing infectious viral organism or, in case of a therapeutic vaccine, to treat or alleviate infection against the lipid-containing infections viral organism. The vaccine compositions of the present invention include combination vaccines of modified viral particles obtained from one or more strains of a virus and/or one or more types of virus.
  77. 77. Issues related to Expression systems Axel Patent Story !!!! Columbia University 4/6/2014 77RD_Vaccine Meet_2014
  78. 78. 4/6/2014 RD_Vaccine Meet_2014 78 AXELPatentStorey:ColumbiaUniversity
  79. 79. IP issues in cells used for Expression Cells Several of these cell lines have been used for many years and hence are not covered by patents and can be obtained from public sources. However, in order to get regulatory approval for vaccines produced in a cell line requires that Master and Working cell banks are established and characterized, a very lengthy and costly process. Manufacturers who have undertaken such processes are unlikely to share their characterized cell line. Hence even in absence of IP on the cell line, there is a significant barrier to the use of these cells. A possible exception to this is the Vero cell line which can be purchased with full characterization. There is IP on specific variants of these strains (e.g. MDCK-B-702 described in US 6825036, a MDCK line with higher susceptibility to infection described in WO 2005/113758), and on the new cell lines including the PerC6 cell lines (e.g. US7192759) and avian embryonic lines (WO 2006/108846). 4/6/2014 79RD_Vaccine Meet_2014
  80. 80. (WO 2006/108846). Cell over expressing a nucleic acid encoding WO 2003/048348 sialyltransferase for production of virus Crucell WO 2005/113758 A MDCK cell with higher susceptibility to viral infection than parenteral line ID biomedical US 6825036 process for preparing MDCK cell in serum-free suspension -specifically MDCK- B-702 line. Kumamoto-ken, JP US 7192759 human embryonic retinoblast cell encoding E1 gene of adenovirus to produce influenza Crucell WO 2006/108846 avian embryonic stem cell. Replicating virus in suspension Vivalis EP 1108787 method for producing flu virus or antigen in cell encoding adenovirus E1 gene. Crucell In addition, as discussed below, there is IP on using cell lines for producing influenza vaccines and also processes involving these cell lines, including the http://www.who.int/vaccine_research/diseases/influenza/Mapping_Intellectual_Property_Pandemic_Influenza_Vaccines.pdf 4/6/2014 80RD_Vaccine Meet_2014
  81. 81. IP on cell culture inactivated vaccine production process US 7132271 method for enhancing production using cell with targeted deletion in PKR or 2-5A gene U. California US 6673591 use of cells with targeted deletion in PKR gene to enhance virus production in cells U. California US 6686190 use of cells with targeted deletion in at least one ISG gene to enhance production in cells U. California WO 1997/008292 process to enhance virus production in cells by inhibiting PKR 2-5a synthetase U. California US 6344354 Vaccine comprising flu virus produced on cells (isolate not been passaged on eggs) St Judes US 6656720 MDCK cell adapted to suspension growth for influenza virus production Novartis US 6455298 use of MDCK 33016 for replication of influenza virus in serum-free medium. EP 870508 process to reduce DNA content in cell derived vaccine by use of DNAse and detergent Duphar US 4500513 influenza vaccine production in liquid cell culture Miles Lab US 5698433 Producing flu vaccine in Avian embryo cells: Infection prior to growth on monolayer. Baxter (Immuno ) US 5753489 producing virus in serum free monkey kidney cells Baxter (Immuno AG US 6146873 producing virus in serum free monkey kidney cells Baxter (Immuno AG US 5756341 producing in serum free monkey kidney cells, with modified cleavage site in HA Baxter (Immuno AG US 5840565 Use of PKR antisense polynucleotide to enhance production of influenza virus in cells U. California WO 2005/024039 Replacing NS gene of APR/8 with NS from A/England to produce high titer virus in cells St Judes WO 2005/028658 two vectors, at least one containing a pol II promotor linked to a ribozyme sequence Wisconsin alumni WO 2006/027698 tests to ensure that no pathogens other than influenza virus are growing in cell culture Chiron Behring WO 2006/067211 use of bacteriophage polymerase promoter to produce influenza antigen in cells Solvay WO 2007/002008 expression vector containing canine RNA polymerase regulatory sequence; MDCK MedImmune WO 2007/045674 method for producing flu virus or antigen in cell encoding adenovirus E1 gene. Crucell US 7037707 method of making a reassortant growing to high titer by using an alternative NS gene St Judes 4/6/2014 81RD_Vaccine Meet_2014
  82. 82. 4/6/2014 RD_Vaccine Meet_2014 82 IP Issues on Vehicles Injection Nanoparticles The living epidermis and dermis are rich in antigen presenting cells (APCs). Their activation can elicit a strong humoral and cellular immune response as well as mucosal immunity. Therefore, the skin is a very attractive site for vaccination, and an intradermal application of antigen may be much more effective than a subcutaneous or intramuscular injection. However, the stratum corneum (SC) is a most effective barrier against the invasion of topically applied vaccines. Products which have reached the stage of clinical testing, avoid this problem by injecting the nano-vaccine intradermally or by employing a barrier disrupting method and applying the vaccine to a relatively large skin area. Needle-free vaccination is desirable from a number of aspects: ease of application, improved patient acceptance and less risk of infection among them. Nanocarriers can be designed in a way that they can overcome the SC. Also incorporation into nanocarriers protects instable antigen from degradation, improves uptake and processing by APCs, and facilitates endosomal escape and nuclear delivery of DNA vaccines. In addition, sustained release systems may build a depot in the tissue gradually releasing antigen which may avoid booster doses. Therefore, nanoformulations of vaccines for transcutaneous immunization are currently a very dynamic field of research. Among the huge variety of nanocarrier systems that are investigated hopes lie on ultra-flexible liposomes, superfine rigid nanoparticles and nanocarriers, which are taken up by hair follicles. The potential and pitfalls associated with these three classes of carriers will be discussed.
  83. 83. 4/6/2014 RD_Vaccine Meet_2014 83 IP Issues in Vaccination using gold nano- particles 26 June 2013 | Source: Nanotechnology Scientists in the US have developed a novel vaccination method that uses tiny gold particles to mimic a virus and carry specific proteins to the body’s specialist immune cells. The technique differs from the traditional approach of using dead or inactive viruses as a vaccine and was demonstrated in the lab using a specific protein that sits on the surface of the respiratory syncytial virus (RSV). The results have been published today, 26 June 2013, in IOP Publishing’s journal Nanotechnology by a team of researchers from Vanderbilt University. RSV is the leading viral cause of lower respiration tract infections, causing several hundred thousand deaths and an estimated 65 million infections a year, mainly in children and the elderly. The detrimental effects of RSV come, in part, from a specific protein, called the F protein, which coats the surface of the virus. The protein enables the virus to enter into the cytoplasm of cells and also causes cells to stick together, making the virus harder to eliminate.
  84. 84. 4/6/2014 RD_Vaccine Meet_2014 84 IP issues in Bio-manufacturing/NO COLD CHAIN VACCINES The nanopatch is designed to place a tiny amount of vaccine just under the skin without the need for a needle jab. Because it delivers the active ingredient right to where it is needed, tests have shown it can generate the same immune response with only a fraction of the dose needed in a conventional vaccine. Among other potential advantages of the nanopatch are that it is pain free, low cost — it could be made for under $1 a dose compared with more than $50 for many current vaccines — and easily transportable. Kendall (biotech company given grant by Merck) even ponders whether it might be mailed to remote places for people to administer it themselves
  85. 85. 4/6/2014 RD_Vaccine Meet_2014 85 IP issues in Delivery Systems
  86. 86. 4/6/2014 RD_Vaccine Meet_2014 86 Merck & Co. to Evaluate Transdermal Vaccine Delivery System Merck & Co. and vaccine delivery specialist Vaxxas started a research collaboration focused on evaluating the use of the latter’s transdermal Nanopatch™ vaccine delivery system with a Merck vaccine candidate. Under terms of the deal Australian firm Vaxxas will receive an up-front fee, research funding, and option fees if Merck exercises its option to the platform for the development and commercialization of vaccine candidates for up to two additional fields. Vaxxas will also be eligible for development and regulatory milestone payments. Vaxxas’ Nanopatch™ vaccine delivery technology consists of a 1 cm2 silicone array that carries about 20,000 vaccine-coated microprojections that painlessly perforate the outer layers of the skin when applied with the associated applicator device, and deliver the vaccine directly to key immune cells immediately below the skin surface. The firm believes the system can significantly enhance the therapeutic potential of both existing and new vaccine candidates by amplifying efficacy, reducing the required dose, and obviating the need for adjuvants, as well as preventing needlestick injuries and cross-contamination. Preclinical in vivo studies showed that use of Nanopatch allowed a 100-fold reduction in the required dose of Fluvax® influenza vaccine. The applicator device used with the Nanopatch array has in addition been designed to achieve uniform penetration and delivery across the range of natural variations in skin structure associated with age, gender, and health, and overcome the inconsistencies associated with other transdermal vaccine delivery approaches, Vaxxas claims. Founded in August 2011 with a Aus$15 million venture capital investment (about $15.3 million at today’s exchange rate), Vaxxas’ platform was originally developed by researchers at UQ’s Australian Institute for Bioengineering and Nanotechnology. http://www.genengnews.com/gen-news- highlights/merck-co-to-evaluate-transdermal- vaccine-delivery-system/81247449/
  87. 87. Issues related to Immuno-stimulatory sequences Background: Recent studies have demonstrated that bacterially derived immunostimulatory sequences (ISSs) of DNA can activate the mammalian innate immune system and promote the development of TH1 cells. Promotion of TH1 immunity by means of immunotherapy in allergic patients has led to the alleviation of symptoms that result from allergen-specific TH2 responses. Objective: Our purpose was to investigate whether the TH1- enhancing properties of ISSs could be used to alter the TH2-dominated immune response of allergic PBMCs in vitro. Methods: Ragweed protein-linked ISS (PLI) was generated from a specific, highly active 22-base ISS and Amb a 1, the immunodominant allergen in ragweed pollen, to combine the TH1-enhancing properties of ISSs with allergen selectivity, and its activity was investigated in PBMC cultures from subjects with ragweed allergy. Results: PLI was markedly successful at reversing the dominant allergen-induced TH2 profile while greatly enhancing IFN-γ production. Delivering ISSs in a linked form proved to be much more effective at modulating the resulting cytokine profile than delivering free ISSs in a mixture with unlinked Amb a 1. PLI also demonstrated cytokine-modulating properties, even when used to stimulate cells that had already been primed for 6 days with Amb a 1. The antigen specificity of the action of PLI was confirmed by the observations that PLI enhances Amb a 1–specific T-cell proliferation. Conclusion: These data indicate that delivery of ISSs within an antigen-specific context exhibits potent cytokine-modulating activity and, combined with its reduced allergenicity, makes this molecule a strong candidate for use in improved immunotherapy applications. (J Allergy Clin Immunol 2001;108:191-7.) 4/6/2014 87RD_Vaccine Meet_2014
  88. 88. 4/6/2014 RD_Vaccine Meet_2014 88 Plant Derived vaccines A new category of technology which may confound existing IP regimes is plant derived vaccines (“PDVs”). The make-up of this innovation is just as its name suggests – a vaccination product derived from plants. Although there is no trick to understanding the nature of PDVs, deciding which IP regime may be utilized to protect this invention can prove to be troublesome. Due to the fact that the technology ties together several elements which have previously stood alone as distinct technological categories, PDVs fit simultaneously within several existing categories, each of which offers unique aspects of protection. In basic terms, a PDV is a plant variety, a drug, a biotechnological innovation and a developing nation- focused product all-in-one. It is therefore difficult to categorize PDVs for the purpose of IP protection.
  89. 89. What will happen, if vaccines will be derived from proprietary variety?? The decision of the Supreme Court of the United States on Merck v. Integra Life Sciences in 2005, analysts contend that, with the broadened definition by the Supreme Court of the Hatch-Waxman Act as it relates to data exclusivity, research in preparation of FDA approval is exempt from the requirement for research licenses 4/6/2014 89RD_Vaccine Meet_2014
  90. 90. 4/6/2014 RD_Vaccine Meet_2014 90 Will Vaccines Derived from Plants be Classified under Drugs or Foods? Ans: Both – so IP issues become more complex
  91. 91. 4/6/2014 RD_Vaccine Meet_2014 91 Biotechnology products can benefit from both trade secret and patent protection. Each of these forms of IP are haunted by considerations beyond the bounds of pure science, which arise in conjunction with the clinical trials and commercialization stages in particular. These include ethical, social and cultural concerns. In the words of E. Richard Gold and Wendy A. Adams, “the health benefits to individual recipients of the products of biotechnological innovation are self evident, although far from uncontroversial.” Others have voiced concerns as to whether extending strong IP rights to biotechnological innovation is ethical, or even legally defensible. Specific issues raised by PDVs include liabilities related to the growth of transgenic plants and the production of drugs from these materials. BIO has acknowledged that steps must be taken to minimize the risks associated with the production of plant based genetically modified health technologies, including control of exposure to transgenic plants and their expression products. BIO’s caution is the type of issue that will likely be addressed through regulation or policy initiatives to restrict the growth of plants to confined facilities and to ensure that processing, milling and extraction of transgenic plant materials is undertaken separate from commercial food and feed channels. These represent physical protections which may be achieved. Recent case law has examined the legal protections available, through a review of the validity and scope of claims which form the basis of patent rights held in biotechnology inventions.
  92. 92. Issues of IP on Antigens VACCINE COMPONENT ROYALTY ON SALES OF VACCINE Antigen A, Proprietary to Company A 2% Antigen B, Discovered with proprietary tool of Company B 2% Antigen C, Nonproprietary 0% Proprietary assembly technique of Company C 2% Proprietary adjuvant 2% 4/6/2014 92RD_Vaccine Meet_2014
  93. 93. IP Issues: Vaccine composition Component Purpose Example Adjuvants enhance the immune response to a vaccine aluminium salts Preservatives prevent bacterial or fungal contamination of vaccine thiomersal Additives stabilise vaccines from adverse conditions such as freeze-drying or heat, thereby maintaining a vaccine’s potency gelatine Residuals from manufacturing process Inactivating agents Antibiotics - prevent bacterial contamination during manufacturing process Egg proteins- some vaccine viruses are grown in chick embryo cells Yeast proteins formaldehyde neomycin, streptomycin, polymyxin B influenza, yellow fever HepB vaccine 4/6/2014 93 RD_Vaccine Meet_2014
  94. 94. cDNA clones Methods of treatment Human monoclonal antibodies Compounds genetic variants Agonist and antagonist peptides Method for production and purification Highly active glycoproteins-process conditions and an efficient method for their production Nucleic-acid programmable protein arrays Detection of adventitious agents Compositions and methods for extracting and using vaccines composition containing synthetic adjuvant Antibodies as vaccines Vaccine formulations Combinations of clades as in pneumococcal treatment Compositions of PD-1 antagonists and methods of use Inhibitors of angiopoietin-like 4 protein, combinations, and their use Chemically programmable immunity use in gene modulation in vaccine development Compositions and methods of enhancing immune responses Humanized antibody compositions and methods Influenza inhibiting compositions and methods Compositions and methods modulating MG29 for the treatment of diabetes Methods of generating libraries and uses thereof Process for improved protein expression by strain engineering Process for large scale production of plasmid DNA by fermentation Method for producing storage stable viruses and immunogenic compositions thereof Prostate carcinogenesis predictor Antigen surrogates in autoimmune disease Anti-avian influenza virus agent, and product containing anti-avian influenza virus agent Compositions and methods for frozen particle compositions Immunoconjugates, methods and uses Simian adenovirus nucleic acid and amino acid sequences, vectors containing same, and methods of use Genetic adjuvants for immunotherapy Composition for prevention of influenza viral infection comprising tannic acid, air filter comprising the same and air cleaning device comprising the filter4/6/2014 94RD_Vaccine Meet_2014
  95. 95. 4/6/2014 RD_Vaccine Meet_2014 95 Bode C. et al. (2011) CpG DNA as a vaccine adjuvant. Expert Rev Vaccines. 2011 April; 10(4): 499–511
  96. 96. R&D Efforts in Adjuvants • The project of extracting a new vaccine adjuvant from 'Ashwagandha' (Withania somnifera), a medicinal plant used in Ayurveda as an immunity enhancer, was sponsored by the Department of Science and Technology and was jointly executed by the researchers from Pune based Serum Institute of India (SII) and University of Pune's Inter-disciplinary School of Health Sciences (ISHS). • The researchers already received a patent on this in India in 2007, but the US patent was granted on August 6, 2013. • The adjuvant extracted from Ashwagandha is believed to improve vaccine efficacy. Further, the adjuvant showed properties where it could be useful in new vaccine development such as the pentavalent vaccine targeting meningitis, or those against dengue, pneumococcal diseases, polio, diphtheria, tetanus and hepatitis and also holds promise against HIV, tuberculosis and malaria. • The researchers have clarified that unlike earlier instances where companies tried to patent turmeric, for example, the patent here was in an area not claimed by Ayurveda. 4/6/2014 96RD_Vaccine Meet_2014
  97. 97. IP issues in Excipient 4/6/2014 97RD_Vaccine Meet_2014 Adenovirus sucrose, D-mannose, D-fructose, dextrose, potassium phosphate, plasdone C, anhydrous lactose, micro crystalline cellulose, polacrilin potassium, magnesium stearate, cellulose acetate phthalate, alcohol, acetone, castor oil, FD&C Yellow #6 aluminum lake dye, human serum albumin, fetal bovine serum, sodium bicarbonate, human-diploid fibroblast cell cultures (WI-38), Dulbecco’s Modified Eagle’s Medium March, 2011 Anthrax (Biothrax) aluminum hydroxide, benzethonium chloride, formaldehyde, amino acids, vitamins, inorganic salts and sugars December, 2008 BCG (Tice) glycerin, asparagine, citric acid, potassium phosphate, magnesium sulfate, Iron ammonium citrate, lactose February, 2009 DT (Sanofi) aluminum potassium sulfate, peptone, bovine extract, formaldehyde, thimerosal (trace), modified Mueller and Miller medium December, 2005 http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/appendices/b/excipient-table-2.pdf
  98. 98. IP issues in Delivery Devices 4/6/2014 98RD_Vaccine Meet_2014
  99. 99. 4/6/2014 RD_Vaccine Meet_2014 99 Strategy : Contribution by PATH  Advancing novel vaccine formulations and processing methods.  Evaluating the technical and commercial feasibility of improving vaccine thermo-stability.  Reducing needle stick injuries by developing immunization devices that shield or eliminate needles.  Creating inherently simple and easy-to-use devices and user aids that improve safety and ease immunization logistics.  Addressing issues of cost by developing and testing effective devices that enable delivery of a reduced dosage of vaccine and help to decrease vaccine wastage.  Improving vaccine presentations and packaging to meet user needs and minimize environmental impact.  Developing and facilitating access to new equipment that stores, monitors, and transports vaccines at appropriate temperatures.  Analyzing the cost-effectiveness of various immunization strategies and interventions to facilitate decision-making.
  100. 100. 4/6/2014 RD_Vaccine Meet_2014 100
  101. 101. 4/6/2014 RD_Vaccine Meet_2014 101 Indian Vaccine Strength http://www.slideshare.net/fababioasia/vaccines- indias-strength-8501392
  102. 102. 4/6/2014 RD_Vaccine Meet_2014 102 Work Around to break Barriers to Existing Vaccines for development of Generic Vaccines w.r.t. basic vaccines Use of pertactin/69K in acellular pertussis vaccine – GSK / Medeva – Work-around: don’t include it (FHA/PT)  Combination vaccines containing low doses of T,P, etc – Use higher doses etc. Stick to 'old' formulation or develop work- arounds – Requires R&D capacity (Source: WHO) Repositioning in Drugs**
  103. 103. 4/6/2014 RD_Vaccine Meet_2014 103 Original Drug Repositioned Development Product Development Approved Repositioned Product Subject to Generic/Modified Competition Original API Patent (20 years) New Use Indication Patent (20 years) 5 yr NCE Exclusivity 14 years extended Patent Life 30 month stay Approval of Repositioning Product (Source: Drug Discovery Today: Therapeutic Strategies Vol.8(3-4), 135, (2011) Subject to ANDA/505(b)2 Patent Challenge Upto 5yr Ext Shelved API Never Previously Approved NCE New Indication Illustration of exclusivities for repositioned product based on shelved API CanthisStrategybetriedforVaccines&Biologics?
  104. 104. 4/6/2014 RD_Vaccine Meet_2014 104 Solutions to tackle barriers
  105. 105. 4/6/2014 RD_Vaccine Meet_2014 105 Solutions Benchmarks on benefit sharing in the Nagoya protocol (not verbatim) 1. Monetary benefits may include, but not be limited to: Access fees/fee per sample collected or otherwise acquired; Up-front, milestone, royalty payments; Licence fees in case of commercialization; Special fees to be paid to trust funds supporting conservation and sustainable use of biodiversity; Salaries and preferential terms where mutually agreed; Research funding; Joint ventures and joint ownership of relevant intellectual property rights. 2. Non-monetary benefits may include, but not be limited to: Sharing research and development results and contribution to local economy; food and livelihoods; Social recognition; Joint ownership of relevant intellectual property rights.
  106. 106. 4/6/2014 RD_Vaccine Meet_2014 106 Disruptive Innovations to tackle IP barriers in generic vaccines Generic drug formulators tend toward what is tried and true, patents are built on a foundation of the unexpected, and planning for the unplanned requires special talents. Our scientists should exhibit success as inventors as a result of combination of extensive experience, out-of-the-box creativity, attention to the details of experimental outcomes, and perseverance. India should look at every problem in the drug development pathway as a potential opportunity to invent and protect.
  107. 107. 4/6/2014 RD_Vaccine Meet_2014 107 Pool Data
  108. 108. 4/6/2014 RD_Vaccine Meet_2014 108 Indian Capacity to deliver Complex Vaccines Starting with a few public-sector manufacturers in the late 1960s India has emerged as the major supplier of basic Expanded Programme on Immunization vaccines to the United Nations Children's Fund (UNICEF) because of substantial private-sector investment in the area. The Indian vaccine industry is now able to produce new and more complex vaccines such as the Meningitis, Haemophilus influenzae type b, and Pneumococcal conjugate vaccines, Rotavirus vaccine and Influenza A (H1N1) vaccines.
  109. 109. 4/6/2014 RD_Vaccine Meet_2014 109 Balancing Act
  110. 110. 4/6/2014 RD_Vaccine Meet_2014 110 We need to balance IP issues with Purchasing Power of the sick & needy?? India needs to further strengthen its IP protection mechanism and speed up examination process. However, when it comes to development of new interventions for Type II and III diseases, it is suggested that these be registered with the appropriate government body, and not much emphasis be placed on complete IP protection before an intervention is produced. This process would ensure that it acknowledges the inventors or funding agencies for their inventions yet reaches the needy quickly. It also needs to be borne in mind that for public interest, choices of IP management should be accordingly exercised, and should not be in conflict with public good.
  111. 111. 4/6/2014 RD_Vaccine Meet_2014 111 Policy Issues The American Association of Universities, for example, has sought to create further barriers to access by encouraging 12 years of data exclusivity for follow-on biologics as part of legislation under consideration in Congress. This is in contrast to the five years of data exclusivity in place for small molecule drugs, and despite the facts that the mean development time for biologics is only 7.4 months longer, and the break-even lifetimes are virtually identical. This stance, which would bolster companies’ bottom lines, threatens to unduly delay the onset of cheaper follow-on biologics after patent expiration. http://www.med4all.org/fileadmin/med/pdf/2_Crager_ Formatted_June3_HPV-Impfung.pdf
  112. 112. 4/6/2014 RD_Vaccine Meet_2014 112 TRIPS Compliance INDIA: At the start of the Uruguay Round negotiations in 1986, over fifty countries did not recognize product patents on pharmaceuticals. The adoption of TRIPS caused a seismic shift in the global IPR regime, raising barriers to generic entry by blocking producers from finding alternative, lower-cost means of producing the same drug. Patent protection of the end product could trump inventions over the process of manufacturing generic versions of the drug. Nowhere has this been of greater concern than in India, which came into TRIPS compliance in 2005. For low- and middle income countries, Indian generic manufacturers supply more than eighty percent of antiretroviral drugs and nearly ninety percent of the pediatric market for such drugs. However, since several key second- and third- line antiretroviral drugs (ARVs) have recently come under patent protection in India, it is not likely that Indian generic competition will be able to reduce the global prices for ARVs at the rates seen for the first-line drugs. THAILAND: The use of the TRIPS flexibilities, such as compulsory licenses, can lead to significant cost savings and increases in coverage. Thailand’s compulsory license on efavirenz was expected to halve the drug price and provide an additional 20,000 patients with the drug under the same budget. Generic imports of the second-line ARV, Kaletra (lopinavir/ritonavir), under compulsory license were also expected to cut the price by over eighty percent, allowing an additional 8,000 patients to access the drug. A comparison of the market prices for the branded originator drugs at the time of the compulsory licenses with the prices of the imported generic equivalents demonstrate a sixty-six percent reduction in price for efavirenz and seventy percent for lopinavir/ritonavir. It is expected that the prices of the cancer drugs will be between three percent and twenty-five percent of the prices for the patented drugs
  113. 113. 4/6/2014 RD_Vaccine Meet_2014 113 Reduction of Complexity by Sharing Information Even in presence of patents, the emergence of markets for technology is not straightforward because there are still major obstacles to such markets (Teece, 1986). To respond to a need for lower transaction costs on technology markets, new actors have recently emerged – such as Innocentive, Yet2.com, and Ocean Tomo - often assisted by new information and communication technologies. The role of those patent brokers is to organize and facilitate exchanges between technology sellers and buyers. To do so, they provide technical assistance, audit, and perform diagnostic tests to assess the value of a given technology. Most importantly, they facilitate the circulation of information (Yanagisawa and Guellec, 2009; Dushnitsky and Klueter, 2011). http://timreview.ca/article/502#sthash.LNJdhZ1s.dpuf
  114. 114. 4/6/2014 RD_Vaccine Meet_2014 114
  115. 115. 4/6/2014 RD_Vaccine Meet_2014 115 Compulsory Licensing to get Generic Vaccines going?
  116. 116. 4/6/2014 RD_Vaccine Meet_2014 116 https://www-935.ibm.com/services/uk/igs/pdf/g510-6342-00-5barriers-etr.pdf (modified) Breaking Innovation to access Barriers Techno-scientific Barriers: Human Resource Barriers Organizational barriers:  Inadequate funding,  Risk avoidance,  “Siloing,”  Time commitments  Incorrect measures Bad Business Practices
  117. 117. 4/6/2014 RD_Vaccine Meet_2014 117 Summary of R&D challenges • The current, market-based R&D system has failed to develop vaccines for diseases such as TB and malaria that affect large numbers of people as well as vaccines for smaller markets such as dengue or Meningitis A. In addition to new vaccines, there is also a need for improved, cheaper, and more suitable versions of existing vaccines. • Although there has been progress and a number of promising initiatives, these efforts still depend too much on the established multinational firms, who fund and conduct most late-stage vaccine R&D. There is a great opportunity to exploit and expand developing country capacity to develop needed vaccines. • Much vaccine technology is initially developed in government and academic institutions, but these inventions are typically licensed to big pharma for rich-world applications. • New mechanisms are needed to support technology transfer and fund vaccine development.
  118. 118. 4/6/2014 RD_Vaccine Meet_2014 118 “With all this background, contribution of Industry, Academia, NGOs, Governments, and health care professionals should not be underestimated We need to be tolerant and do the balancing act between various stake-holders for global health issues” RD-2014
  119. 119. 4/6/2014 RD_Vaccine Meet_2014 119 Thanks (rdhar_in@yahoo.com)