Intellectual Property, Technology Transfer and Developing Country Manufacture of Low-cost HPV vaccines - A Case Study of India

Cervical cancer, the leading cause of female cancer mortality worldwide, disproportionately affects women in low- and middle-income countries (LMCs). Four-fifths of the nearly 275,000 annual cervical cancer-related deaths occur in LMCs where routine gynecological screening is minimal or absent.^1,2 Two new prophylactic vaccines, Gardasil® from Merck and Cervarix® from GlaxoSmithKline (GSK) have proven effective in preventing HPV-induced cervical lesions and some sequelae. Composed of HPV-L1 major capsid antigen virus-like particles (VLPs), both vaccines prevent persistent infection from HPV-16 and -18, strains that cause nearly 70% of cervical cancers.³ Gardasil also contains L1 antigens from HPV strains -6 and -11 associated with genital warts. Costing at least $300 for the 3-dose regimen, Gardasil is one of the most expensive vaccines introduced to date.⁴ Its private market price exceeds $500 in several developed and developing countries,⁵ which few can afford in most LMCs.^{1,6, 7}

Price discrimination by pharmaceutical companies could improve vaccine access in LMCs. Merck introduced Gardasil in India at about $171 for the three-dose regime.⁸ While such pricing enables middle-class access in some emerging economies, the vaccine remains unaffordable for most low- and middle-income populations in LMCs. Prices must fall below $2/dose to enable broad access in low-income populations, especially in countries with GDP/capita below $1000.^9,10 It is unlikely that Merck or GSK can reduce vaccine prices to match these affordability targets because of high production costs associated with their vaccines.¹¹ Company donations may also improve access.^{12, 13} Merck has donated 3 million doses of Gardasil to the Program for Appropriate Technology in Health (PATH) for demonstration trials.¹⁴ Its Gardasil Access Program aims to extend this support to eight LMCs.¹⁵ However, reliance on pharmaceutical company donations alone is unsustainable. Alternatively, donor-aided vaccine purchase can significantly increase vaccine access by facilitating distribution of highly discounted vaccines in eligible LMCs.¹⁶ The Global Alliance for Vaccines and Immunization (GAVI) recently prioritized HPV vaccines.¹⁷ However, due to a US$4 billion deficit and prior financial commitments to other vaccines, it may be unable to finance HPV vaccines.¹⁸ Donors often face tradeoffs and high prices limit the quantities of vaccines/treatments they can subsidize.¹⁹

Vaccine manufacturing in LMCs can also reduce prices. Over the past decade, manufacturers in India, Cuba, China, and Brazil have demonstrated their capacity to produce low-cost vaccines that meet international quality standards. They primarily serve low-income markets, supplying 64% of childhood vaccines procured by UNICEF and 43% of vaccines procured by GAVI.^20,21 Recombinant Hepatitis B (HBV) vaccines illustrate the potential impact of such manufacturers in improving vaccine access in LMCs. When introduced in the early 1980s, the HBV vaccine was priced at $50-80/dose, one of the most expensive prophylactic vaccines at that time.²¹ However, Developing Country Vaccine Manufacturers (DCVMs), using alternate expression platforms suitable for low-cost development, successfully brought inexpensive HBV vaccines to market in the 1990s. The ensuing competition reduced market prices to less than $0.30 per dose.^{22, 21} Procurement costs for large vaccination programs consequently decreased, allowing wider vaccine access in LMCs.²¹ DCVMs are therefore potentially important suppliers of low-cost HPV vaccines.

For successful production, DCVMs require access to relevant technology, which may be protected by intellectual property (IP) rights. Although DCVMs have faced few patent barriers to date, changes adopted by developing countries to comply with the World Trade Organization’s Agreement on Trade Related Aspects of Intellectual Property Rights (TRIPs) may create new obstacles for vaccine development.23 Before TRIPs, many LMCs did not award product patents for biopharmaceuticals, including vaccines. Now, however, DCVMs must consider international pharmaceutical companies’ product patent rights on vaccines and related technologies. Patents granted in developing countries may constrain manufacturers’ ability to: (1) develop vaccines, and/or (2) sell vaccines in local and international LMC markets (Figure 1), thus reducing their development incentives.

Figure 1. Impact of patents on manufacturing, sale, and/or export of “bio-similar” HPV vaccines by developing country vaccine manufacturers.

Patents existing in the country of the manufacturer that claim the “composition of matter” of necessary antigens (e.g. nucleic acid and/or amino acid sequences of the L1 proteins) or the vaccine itself (e.g. VLPs made of L1 antigens) would prevent DCVMs from developing and selling vaccines in their country without a license from the patent owner. If, however, patents only claim specific methods or processes for producing the vaccine, manufacturers may have freedom to operate if they use alternate processes to “work around” those patents. Patents granted in jurisdictions outside the manufacturing country – especially in potential export markets – may also affect DCVM vaccine development plans. Manufacturers exporting vaccinesto these countries would infringe patents if their vaccines embodied the compositions or processes protected by such patents. However, if vaccines had different formulations or were developed by using alternate processes, they could still be sold in the importing country.

Two recent reports suggest that IP may be a barrier for DCVMs interested in developing HPV vaccines.^{24, 25} However, publicly available information about the patenting and licensing of HPV vaccine technologies in developing countries is minimal. We therefore systematically examined the extent to which patents are a barrier to producing HPV vaccines in LMCs, focusing on India for several reasons. India bears nearly 25% of the global cervical cancer burden^{26, 27} and its growing middle class is a potentially large private market for HPV vaccines. Including this vaccine in national immunization programs targeting low-income populations will further expand the market, creating strong incentives for local manufacturing of inexpensive alternatives. Additionally, several Indian manufacturers interested in developing HPV vaccines have concerns about potential patent impediments to such efforts.

The HPV vaccine Patent Landscape

1. First generation prophylactic vaccines

Enabling technologies for L1-VLP-based vaccines originated at the National Cancer Institute (NCI, USA), University of Rochester, Georgetown University, and the University of Queensland (Australia) (Table1). MedImmune, Merck and GSK developed these technologies further and performed safety and efficacy clinical testing to bring the vaccines to market.²⁹ The IP landscape for HPV vaccines is complex, with 81 US patents granted to date, corresponding to 86 PCT applications. 18 entities – 10 of which are non-profit – own these US patents. Non-profits own 20 of the 81 US patents, for-profits own 55, and for-profit and non-profit entities jointly own 6 (Supplemental Data Table 1). Merck owns the most patents, 24, followed by GSK and the US Government (arising from the NCI), who own 8 patents each.

Table 1. Timeline of Patenting and Licensing of HPV L1-VLP based prophylactic vaccines.

Technologies underlying the L1-VLP based prophylactic vaccines emerged from research conducted at the University of Rochester (USA), the National Cancer Institute, NIH (USA), Georgetown University (USA) and the University of Queensland (Australia). Ian Frazer et al. of Queensland first published their findings in November 1991 in Virology. Richard Schlegel et al. (Georgetown) subsequently published their findings in Virology in September 1992 followed by Robert Rose et al. (Rochester) in April 1993. John Schiller and Douglas Lowy et al. (NCI) published in the Proceedings of the National Academy of Sciences on December 15, 1992. The NCI initially non-exclusively licensed the technology to MedImmune and Merck. MedImmune also acquired worldwide exclusive rights to intellectual property from Georgetown University and the University of Rochester. The University of Queensland licensed its patents to CSL, which in turn licensed the technology exclusively to Merck. GSK eventually acquired exclusive rights to MedImmune’s entire IP portfolio for HPV vaccine development. Due to a first-to-invent system in the US, patent interference proceedings were triggered at the USPTO when claims overlapped from different patent applications filed by four different groups of inventors. The interference proceedings involved various L1-antigen HPV-related claims. Six two-way patent interferences between the four parties continued for nearly a decade, presumably at significant cost to the institutions or their primary licensees and were partially resolved in 2005. Given the uncertainty surrounding the ownership of enabling vaccine technologies, the possibility of mutually blocking exclusive rights (that is, neither firm could be sure its products would not infringe patent rights held by the other) Merck and GSK cross-licensed their respective IP holdings in 2005 to ensure unfettered access to these technologies, consequently securing their market position, in the US and Europe and other OECD nations like Canada and Japan. As part of the financial settlement of the patent interference, the non-exclusive licenses awarded by NCI, NIH to MedImmune and Merck were converted to co-exclusive licenses thus allowing both GSK and Merck access to this intellectual property. Merck brought Gardasil to market in the US in 2006. Cervarix was introduced in the UK in June 2008.

Date	Event
July 19, 1991	Ian Frazer et al. (Queensland) file international patent application in Australia1
June 25, 1992	Richard Schlegel et al. (Georgetown)file patent application in USA1
September 3, 1992	John Schiller and Douglas Lowy et al. (NCI, NIH) file patent application in USA2
March 9, 1993	Robert Rose et al. (Rochester) file patent in USA2
February 1995	University of Queensland’s commercial arm UniQuest licenses HPV vaccine technology to CSL3
October 5, 1995	MedImmune acquires exclusive license to HPV vaccine technology from University of Rochester4
1995	Merck licenses HPV vaccine technology from CSL5
June 26, 1996	MedImmune in-licenses key HPV IP from German Cancer Research Center4
January 7, 1997	NCI non-exclusively licenses HPV vaccine technology to MedImmune6
June, 24, 1997	USPTO declares initial interference2
December 1997	NCI non-exclusively licenses HPV vaccine technology to Merck6
December 11, 1997	MedImmune and SmithKline Beecham form worldwide HPV vaccine alliance4
January 16, 1998	MedImmune finalizes vaccine agreement with SmithKline Beecham4
October 24, 2001	USPTO declares patent interference 104,771 between Rose and Lowy2 USPTO declares patent interference 104,772 between Rose and Schlegel2 USPTO declares patent interference 104,773 between Rose and Frazer2 USPTO declares patent interference 104,774 between Lowy and Schlegel2 USPTO declares patent interference 104,775 between Lowy and Frazer2 USPTO declares patent interference 104,776 between Schlegel v. Frazer2
February 2005	Merck and GSK enter cross-license agreement for HPV patents7
May 2005	NCI’s non-exclusive licenses convert to co-exclusive licenses6
September 20, 2005	USPTO Board of Interference announces decision and awards priority to Schlegel et al 2
December 29, 2005	Frazer et al. appeal USPTO decision, case docketed in CAFC8
August 20, 2007	CAFC reverses USPTO decision and awards priority to Ian Frazer et al. 1

¹Court of Appeals of the Federal Circuit (CAFC). Schlegel v. Frazer. August 20, 2007.

²USPTO Patent Application Information Retrieval. Application No. 08/185/928. http://portal.uspto.gov/external/portal/pair

³David Henderson. Managing Director, Uniquest Ltd, Case Study: HPV Vaccine. Pathways to Innovation – how can we do it better? A submission to the House of Representatives Standing Committee on Science and Innovation. April 29, 2005. www.aph.gov.au/house/committee/scin/pathways/subs/sub27.pdf

⁴A Billich. HPV vaccine (MedImmune/GlaxoSmithKline). Current Opinion in Investigational Drugs 2003. 4: 210–213.

⁵Milan Reiniš. Technology evaluation: HPV Vaccine (quadrivalent), Aventis/MSD/CSL. Current Opinion in Molecular Therapeutics. 2004. 2:206–211.

⁶Personal correspondence. Michael Shmilovich, Esq. Office of Technology Transfer, NCI, NIH. October 7, 2008.

⁷Christopher Crum, et al. Quadrivalent Human Papillomavirus Recombinant Vaccines. Nature Reviews Drug Discovery. 2006. 5:629–630.

⁸Information obtained from the CAFC by phone inquiry. August 26, 2009.

As of December 2008, 18 of the 86 international applications were filed in India (Table 2). The universities and NIH have not sought patent protection for technologies underlying L1-VLP vaccines in India. Merck and GSK however, have applied for patents on HPV vaccine compositions. GSK alone has filed 13 of these applications. The IPO has awarded 6 patents, 4 to GSK and 1 each to Wyeth Holdings Corp. and the University of Cape Town (South Africa). While determination of patent scope is complicated and sometimes the subject of costly litigation, we offer our preliminary analysis of patent claims based on our understanding of these technologies and discussions with researchers who developed first generation vaccines. Patent 203333 awarded to GSK claims compositions of a prophylactic vaccine that contains VLPs composed of L1 antigens from HPV 16, 18, 31, and 45. This is detailed in Claim 1, the first independent claim that technically confers the broadest scope of protection and reads “ A vaccine composition comprising viral like particles containing L1 proteins or functional l1 protein derivatives from human papilloma virus 16, human papilloma virus 18, human papilloma virus 33 and human papilloma virus 45 genotypes wherein the antibody response generated by the vaccine is at a level similar to that for each human papilloma virus, virus like particle formulated alone.” Our analysis suggests that only a vaccine containing L1-VLPs from all four HPV strains mentioned in Claim 1 directly infringes the patent. Therefore, Indian manufacturers are likely free to develop a bivalent HPV vaccine containing L1-VLPs for HPV-16 and -18 only or a quadrivalent vaccine containing any combination of three, two, or one of these four strains in addition to other unclaimed oncogenic strains. Patent 209780, also awarded to GSK, claims a vaccine composition comprising L1-VLPs for HPV-16, HPV-18 and an adjuvant containing aluminum hydroxide and 3-0-desacyl-4'-monophosphoryl lipid A (3dMPL). Claim 1 specifically reads, “A vaccine comprising a human papillomavirus 16 L1 Virus like particles, human papillomavirus 18 L1 virus like particle, aluminum hydroxide, and 3dMPL. Furthermore, Claim 4 reads, “The vaccine consisting of an HPV 16 L1 VLP, an HPV 18 L1 VLP, aluminum hydroxide, and 3dMPL. However, our analysis suggests that a bivalent (HPV-16, -18 L1-VLP) prophylactic vaccine developed by an Indian manufacturer would not infringe this patent if formulated with a different adjuvant. Additional patents awarded to GSK (Table 2) claim nucleotide sequences of HPV early antigens (214047) and compositions of combination vaccines containing HPV L1 antigens (202425) and other antigens respectively. These too are unlikely to constrain Indian vaccine manufacturers developing Gardasil or Cervarix “biosimilars.” The University of Cape Town patent claims methods to produce HPV-16 L1-VLPs in tobacco plants and their use in a vaccine composition. However, to date plant-based expression has been unsuccessful in yielding high amounts of purified HPV-16 VLPs,¹¹ thus limiting the commercial viability of this technology. Patent 220842 awarded to Wyeth covers polypeptides of HPV early antigens E6 and E7, which are likely to be used in therapeutic cervical cancer vaccine compositions but are less relevant to L1-VLP-based prophylactic vaccines. We found no patents on HPV 16 and HPV 18 L1 nucleic acid sequences filed or awarded in India. However, Merck has 4 pending patent applications, claiming L1 nucleic acid sequences of HPV subtypes 31, 45, 52, and 58, optimized for expression in several yeast strains. However, the IPO may choose to significantly narrow the scope of or deny some claims during examination. It is therefore difficult to assess whether Merck’s application will affect vaccine development in India.

Table 2. Patent Landscape for HPV Vaccines in India.

The Delphion™ patent database was searched for HPV vaccine-related patents and patent applications published on or before December 31, 2008 using “inventor” and “assignee” names. These results were supplemented with searches of other databases (Derwent Patent Index and the World Intellectual Property Office patent database) to find corresponding international applications filed under the Patent Cooperation Treaty (PCT) and national phase information. Indian patent filings were indentified using two freely available resources, the BigPatents²⁸ and Indian Patent Office (IPO) databases. Since neither of the Indian electronic databases included patent claims, we obtained certified hard copies of all granted patents from the four Indian patent offices for claims analysis. For pending Indian applications, we analyzed claims published in corresponding PCT filings. However, there may be pending patent applications not yet published by the IPO that therefore could not be analyzed. We collected information about the licensing status of patents and applications from Securities and Exchange Commission (SEC) filings, and where necessary, directly from patent owners. We identified other legal and/or technological barriers through interviews conducted withHPV vaccine researchers, who developed first- and second-generation vaccines, technologies relevant to vaccine development in India. We also interviewed researchers and business leaders at four Indian companies – Shantha Biotechnics Ltd (Shantha),1 Indian Immunologicals Ltd (ILL), Bharat Biotech Ltd (Bharat) and Serum Institute of India (Serum) – that are developing HPV vaccines.

Assignee/ Applicant	PCT Application No/ International Publication No	Indian Application No. & Application Date in India	Publication Date/ Application Date	Granted Patent No. (Publication Date of Grant)	Expiry Date	Summary of Claims
Glaxo Smithkline Biologicals SA.	PCT/EP2005/006461 (WO 05/123125)	3436/KOLNP/2006	6.15.2007/ 11.20.2006	Pending		-An immunogenic vaccine composition contaning VLPs, and/or capsomeres of HPV 16, 18 and atleast one other HPV genotype
Glaxo Smithkline Biologicals SA.	PCT/EP2003/02826 (WO 03/077942)	1351/KOLNP/2004	12.30.2005/ 9.13.2004	203333 (4.13.2007)	9.13.2024	-An L1 VLP based vaccine composition containing VLPs of HPV16, HPV 18, HPV 31 and HPV 45. -Vaccine composition further comprising complete or immunologically active fragments of HPV early antigens E1–E8. -Vaccine composition further comprising antigens of other STDs including HIV, HSV and Chlamydia.
Glaxo Group Ltd	PCT/GB2001/03290 (WO 02/08435)	67/MUMNP/2003 1561/MUMNP/2007 (Divisional of 67/MUMNP/2003)	2.4.2005/ 1.16.2003 11.9.2007/ 9.27.2007	214047 (1.24.2008) Pending	1.16.2023	-A synthetic polynucleotide sequence, analogue or fragment codon optimized for E Coli and encoding the mutated amino acid sequences of HPV early antigen E1,E2for HPV types/ subtypes selected from HPV1-4, 6,7,10,11, 16,18,26–29, 31,33,35,39,49,51,52,56,59,62 and 68. -A p7313Plc backbone based expression vector capable of driving expression of nucleotide sequences claimed in bacterial cells.
Glaxo Smithkline Biologicals SA.	PCT/EP2006/003918 (WO 06/114312)	3957/KOLNP/2007	6.20.2008/ 10.15.2007	Pending		-L1 proteins of HPV 31, 45, 52 -Method to boost immune response to HPV 16, 18 vaccine by using L1 proteins of other HPV subtypes in composition claimed
Smithkline Beecham Biologicals	PCT/EP/2000/08784 (WO 01/0117551)	1471/CHENP/2003 IN/PCT/2002/336/CHE	11.25.2005/ 9.17.2003 N/A/ 3.5.2002	209780 (9.6.2007) 202425 (4.13.2007)	9.17.2023 3.5.2022	-A vaccine composition comprising HPV 16 L1 VLPs, HPV 18L1 VLPs, Aluminum Hydroxide and 3DMPL. -A vaccine composition for treating or preventing HPV and HSV infections comprising the HSV gsD2 antigen and an HPV 6, 11, 16 or 18 L1 antigen and an adjuvant that stimulates TH1 response
Glaxo Smithkline Biologicals SA.	PCT/EP2003/014562 (WO 04/056389)	1108/KOLNP/2005	7.21.2006/ 6.9.2005	Pending		-Use of a vaccine composition comprising HPV 16 and 18 VLPs to prevent infection by other oncogenic types of HPV excluding HPV 16 and 18.
Glaxo Group Ltd	PCT/EP2003/011158 (WO 04/031222)	506/KOLNP/2005	6.9.2003/ 3.24.2005	Pending		-Nucleotide sequence of HPV polypeptides: E1 or E2 from oncogenic HPV subtypes -Expression vector with codon-optimized polynucleotide sequence -Pharmaceutical composition comprising polynucleotides or vector encoding nucleotide sequence
Glaxo Smithkline Biologicals SA.	PCT/EP2002/04966 (WO 02/087614)	1336/KOLNP/200	1.13.2006/ 10.16.2003	Pending		-A vaccine composition comprising: (a) at least one HIV antigen; and either one or both of (b) at least one herpes HSV antigen and (c) at least one (HPV) antigen selected from L1, L2, E6, E7, or combination thereof.
Smithkline Beecham Biologicals S.A	PCT/EP1998/05285 (WO 99/10375)	1903/MAS/1998	3.4.2005/ 8.24.1998	Pending		HPV 16 or 18 E6 or E7 HPV protein in fusion with Hib, lipoprotein D, or NS I or fragment thereof from Influenza Virus, and LYTA or fragment thereof from S. Pneumoniae
Smithkline Beecham Biologicals S.A	PCT/EP2000/08728 (WO 01/17550)	IN/PCT2002/335/CHE	3.4.2005/ 3.5.2002	Pending		-Multivalent combination vaccine including HPV HPV (L1, L2, E6, E7) antigens, EBV (gp 350) HBV (Sag), Hepatitis A (HM-175 strain) HSV 2 gD VZV antigen (gpl), HCMV antigen (gB685, pp65), Toxoplasma gondii antigen (SAG1 or TG34)
Smithkline Beecham Biologicals S.A	PCT/EP1998/08563 (WO 99/33868)	IN/PCT2000/116/CHE	3.4.2005/ 6.13.2000	Pending		-A vaccine composition of HPV E6 or E7 proteins or fusion of above antigens with others including Hib, lipoprotein D, NS I, Influenza Virus, and LYTA of S. Pneumoniae
Merck & Co. Inc	PCT/EP2004/008677 (WO 04/084831)	4036/DELNP/2005	8.31.2007/ 9.8.2005	Pending		-Codon-optimized nucleic acid sequence encoding HPV 31 L1 and codon-optimized for expression in yeast strains including (s. cerevisiae and. p pastoris) -Vector and host expressing nucleic acid claimed -VLPs of recombinant HPV31 L1 or.L2 proteins or combinations produced in yeast. -Methods for producing VLPs in yeast using above nucleotide sequences
Merck & Co. Inc	PCT/US2005/009199 (WO 05/097821)	5998/DELNP/2006	8.24.2007/ 10.16.2006	Pending		-Codon optimized nucleic acid of HPV 52 L1 for expression in yeast including s. cerevisiae, and p. pastoris. -VLPs of HPV 52 L1, L2 or combination produced in yeast -Method of producing HPV 52 L1 or L2 or combination VLPs in yeast
Merck & Co. Inc	PCT/US2004/037372 (WO 05/047315)	2930/DELNP/2006	8.10.2007/ 5.22.2006	Pending		-Codon optimized nucleic acid of HPV 58 L1 for expression in yeast (s. cerevisiae, h. polymorpha, p. pastoris, k. fragilis, k. lactis, s. pombe) -VLPs of HPV 58 L1, L2 or combination -Method of producing HPV 58 L1 or L2 or combination VLPs in yeast
Indian Immunologicals Ltd	PCT/IB2005/001725 (WO 05/123762)	131/CHENP/2007	8.24.2007/ 1.12.2007	Pending		-HPV 16 L1 nucleic acid sequence codon optimized for expression in prokaryotic organism e. coli, shigella, lactobacillus, mycobacteria, lysteria, or salmonella attenuated strains s. enterica serovar, s. typhimurium, s. typhi -Attenuated strain of micro-organism expressing codon optimized HPV capsid protein from PV 16, 18, 31, 45 -Method For improving immunogenicity of a prokaryotic microorganism, specifically salmonella against HPV 16
University of Cape Town, South Africa	PCT/IB2002/03531 (WO 03/018623)	00831/DELNP/2004	4.27.2007/ 3.31.2004	221817 (7.7.2008)	3.31.2024	-Modified nucleotide sequences encoding HPV16,11 L1 proteins for producing VLPs in plant cells where the plant is Nicotiana Benthamiana -VLPs produced by this method for use in a vaccine to treat or prevent HPV infections in human.
Wyeth Holdings Corporation	PCT/US2003/031726 (WO 04/030636)	505/KOLNP/2005	2.24.2006/ 3.24.2005	220842 (6.6.2008)	3.24.2025	-A fusion polypeptide comprising HPV E6 and E7 antigen polypeptides where the E6 antigen has mutations in amino acids 63 or 106 and the E7 antigen has mutations in amino acids 24, 26 or 91. -A nucleotide sequence encoding the above polypeptide
Active Biotech AB	PCT/SE2000/001808 (WO 01/023422)	IN/PCT/2002/00438/CHE	3.4.2005/ 3.21.2002	Pending		-A carrier for introducing HPV major capsid Ll protein which has been intentionally modified to remove major type-specific epitope(s) that cause production of neutralising antibodies and which raises an protective immune response cross-reactive towards two or more of the group of HPV-Ll proteins comprising Ll proteins of HPV-16, HPV-18, HPV-31 and HPV- 45.
Government of the US (NIH) John Hopkins University	PCT/US2006/003601 (WO 06/083984)	6219/DELNP/2007	8.31.2007/ 8.9.2007	Pending		-A method for inducing broadly cross- neutralizing antibodies against cutaneous and mucosal HPV types in humans comprising by administering immunogenic N terminal peptides of L2 protein

¹ Shantha Biotech became a subsidiary of Sanofi Pasteur in July 2009.

2. Second generation prophylactic vaccines

Currently marketed first-generation vaccines are costly to produce as they use expensive expression systems to produce the L1 antigens. Moreover, both miss several oncogenic HPV strains present in India and other LMCs³⁰ which is particularly problematic when countries lack screening programs necessary to detect cancers not prevented by current vaccines. Researchers at the NCI (John Schiller, Douglas Lowy, Richard Roden and colleagues) and Johns Hopkins University (JHU) have developed an L2 (minor capsid antigen)-based vaccine. This approach would protect against infection by all oncogenic strains and would eliminate the costs of increasing valency of L1-based vaccines.¹¹

NCI and JHU have partnered with Shantha Biotechnics to commercialize this candidate. They jointly filed Indian patent application 6219/DELNP/2007 (Table 2) with the explicit rationale of preserving freedom to operate and market exclusivity for Indian partners.³¹ Shantha has signed a Cooperative Research and Development Agreement (CRADA) with the NIH, gaining access to biological materials like codon-optimized plasmids, know-how and personnel training necessary for developing this vaccine. Shantha has non-exclusively licensed this technology from JHU.³² Using an E.coli expression system to purify L2 antigenic peptides, Shantha hopes to lower development costs, thereby enabling significant vaccine price reduction.^{32, 33}

Indian patent application 131/CHENP/2007 also bears on second-generation vaccine development and is based on research performed at the University of Lausanne (Lausanne), Switzerland. Dr. Denise Nardelli-Haefliger and colleagues demonstrated that recombinant clones of attenuated Salmonella strains expressing HPV-16 and -18 L1 antigens can induce a strong immune response ^34,11 This technology would enable oral or mucosal immunization against HPV-16 and -18 infection. Lower development and implementation costs associated with this oral vaccine make it highly suitable for LMC use. To maximize the potential benefits of this technology to LMCs, Nardelli-Haefliger et al. assigned ownership of enabling IP to Indian Immunologicals Ltd.³⁵ ILL has a memorandum of understanding with Lausanne and has received biological materials, know-how, and training. ILL has also filed international patent applications (Table 2) but will not seek patent protection in OECD markets.³⁶ With assured access to essential patents and know-how, ILL has strong incentives to invest in oral HPV vaccine development. Both vaccines are currently in preclinical phase. Shantha projects a 2015 market entry at an initial price of $15/dose.³⁷ Both manufacturers believe, however, that prices will drop further as vaccine adoption increases, eventually reaching the $1-2/dose price range, making broad access feasible.

Serum Institute of India (Serum) and Bharat Biotech (Bharat) are both also developing L1 VLP-based vaccines. Serum’s candidate will likely be a bivalent HPV-16 and -18 vaccine. The company will seek a non-exclusive license from the NIH for cell lines optimized for high expression of L1 antigens and will non-exclusively license the Hansenula polymorpha expression platform from Rhein Biotech (Germany). Serum anticipates a market entry of three to four years after project initiation.³⁸

In addition to the L1-VLP vaccine, Bharat scientists are exploring a chimeric L2-HPV vaccine. They plan to express an L2-HBV small surface antigen (SAg) fusion protein in Picchea pastoris to produce VLPs containing HPV-L2 antigens at high density. Because the HBV surface antigen spontaneously assembles into VLPs, Bharat hopes to enable vaccine price reduction by circumventing high costs of purifying and assembling VLPs. Bharat filed a provisional patent application for this vaccine in India last year. Despite developing this technology in-house, Bharat may seek a non-exclusive license from the NIH for the cell lines used in neutralizing assays.³⁹

Freedom to Operate

Despite considerable patenting activity, our analysis suggests that IP will not preclude manufacturing of first-generation L1-VLP-based vaccines unless they are identical in formulation or strain coverage to those compositions claimed in granted Indian patents. We cannot, however, make this claim definitively due to uncertainties in interpreting claims and the fate of pending applications. The claims analysis we present is therefore not legal advice but rather a starting point for independent FTO analyses by interested parties. While there are several patents and pending applications on promising second-generation technologies (e.g. L2-based vaccines or oral L1 vaccines), they so far appear to preserve freedom for DCVMs.

IP Transparency

Recent studies suggest that the lack of IP transparency could be a major impediment for DCVMs exploring new vaccine candidates.⁴⁰ Lack of patent claim information in publicly available Indian patent databases made our own research slow and expensive. Our experience mirrored those of Serum⁴¹ and Bharat. Indeed, Bharat’s R&D was delayed due to uncertainty about the status of patent protection for HPV antigens in India.³⁹ 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.

Shantha, ILL, and Bharat often rely on researchers to conduct in-house patent searches.^{33, 36, 39} The WHO Initiative for Vaccine Research or other agencies could help coordinate FTO and patent landscaping services to advise regional manufacturers on potential IP barriers for HPV vaccine development. Creating resources to map and update the IP landscape for novel HPV vaccines could facilitate regional manufacturing efforts. This could be developed in partnership with the Developing Country Vaccine Manufacturing Network.

Potential Roles for Universities and Funders

Universities and non-profit research institutions exploring new HPV vaccine can expedite access to technology in LMCs. As primary generators and gatekeepers of IP for vaccine technologies, academic institution IP management practices will greatly affect regional vaccine manufacturing. The Lausanne-ILL partnership, for example, harnesses DCVM capacity to commercialize a vaccine candidate with potentially high public health impact in LMCs despite little commercial interest in OECD countries. The NCI-JHU-Shantha partnership to commercialize L2-based vaccine technology further illustrates how IP management can create a pathway for product access in low-income markets.

University licensing terms are generally not publicly available, except when parties choose to disclose them voluntarily. This has precluded a definitive analysis of whether Rochester, Queensland, and Georgetown preserved freedom to use these technologies or subsequent improvements in LMCs when negotiating exclusive licenses with Merck and MedImmune (Supplementary Data Table1). However, the licensing of vaccine technologies underlying Gardasil and Cervarix does not conform to recent university technology transfer practice guidelines to maximize benefit for the global poor.^{42, 43} This is understandable because the licenses in question were crafted in the 1980s before these guidelines were developed. Additionally, limited recombinant vaccine production capacity in LMCs rendered humanitarian licensing largely unnecessary at the time. The inaccessibility of HPV vaccines, however, illustrates why recently recommended practice guidelines deserve attention, especially as new technologies for prophylactic or therapeutic vaccines emerge.

Moving forward, universities and other non-profit research institutions should adopt IP management strategies that preserve options for DCVMs. Preferred practices include default non-exclusive licensing, exclusive licenses with geographic fields of restriction (to ensure LMC companies have FTO), retaining rights to sublicense to regional manufacturers, non-profit organizations and/or public-private partnerships, humanitarian use clauses for patented technologies and products, and “White Knight” clauses to ensure vaccine affordability.^{44, 45}

Universities can also help promote IP transparency. Secrecy surrounding licensing exacerbates uncertainties in FTO analyses. Publicly available licensing information can prevent regional manufacturers from wasting time and money on technologies that patents and licenses block. More importantly, illuminating unblocked pathways can create incentives to commercialize vaccines that are of little interest to OECD manufacturers. Universities owning upstream technologies can promote and compel disclosure of licensing terms as part of licensure to improve transparency. Alternatively, sponsors of university research can make transparency a condition of funding by stipulating (1) disclosure of what geographic regions and fields of use exclusive licenses cover or (2) publication of licensing contracts. Regional manufacturers can easily identify technologies available for licensing and potential partners for vaccine development if a central portal or electronic clearinghouse of all HPV vaccine technologies is created.

Technology Transfer: Beyond Patents

While this study focuses on patents, researchers and DCVMs affirm that additional know-how is also crucial for developing new vaccines.²³ Even when technologies are in the public domain or are available for licensing, vaccine development requires considerable expertise.⁴⁶ Universities and other non-profits can address this need by creating collaborative technology transfer partnerships modeled, for example, on the NIH Rotavirus Technology Transfer program.^{47, 48} Transfer of three second-generation HPV vaccine technologies to Indian companies potentially increases the likelihood of producing a vaccine better suited for LMCs than current vaccines. Oral, needle-free delivery of HPV vaccines, for example, might reduce the risk of infection of other sexually transmitted agents like HIV and HSV, eliminate multiple health care visits, and increase patient compliance in resource-poor regions if doses can be administered at home as reconstituted oral drops. Collaborative partnerships with DCVMs may also produce vaccines designed from the onset to meet specific implementation characteristics of resource-poor regions such as heat stable formulations, single-dose, or combination vaccines. Finally, market competition between one or more second-generation vaccines will likely reduce prices.

Conclusions

Experiences with introducing new vaccines suggest that 20 years could pass before women in LMCs gain access to HPV vaccines.⁴⁹ Meanwhile, every five-year delay in vaccine introduction could result in nearly 1.5 to 2 million more HPV-related deaths.¹ Preventing these fatalities will require vaccines that entail fewer doses, minimize interactions with health care professionals, and are suitable for resource-poor setting delivery. Although these are tremendous challenges independent of price, reducing vaccine prices is a necessary step to improve HPV vaccine access. Regional manufacturers can accomplish this by lowering production costs and by developing vaccines tailored for resource-poor settings. Furthermore, increased DCVM competition can lower prices. Our patent landscape suggests that patents on first-generation vaccine do not seriously inhibit DCVM development efforts. Regional manufacturers, national governments, and international agencies should consider this an opportunity and take the necessary steps to make low-cost vaccine production a possibility.

Academic research institutions, from where most HPV vaccine technologies emerged, can play an important role in supporting regional manufacturing. Their technology transfer practices can promote new channels for regional manufacturing while ensuring that licensing does not block pathways to low-cost regional manufacturing of existing vaccines. Improving access to know-how and creating IP transparency can further facilitate regional manufacturing. By participating in technology transfer partnerships and adopting favorable IP management practices, universities can expedite access to new generations of life-saving HPV vaccines and increase the public health impact of these vaccines in LMCs.

Box 1. Mechanisms that enable development of low-cost HPV vaccine by DCVMs.

Create a central portal or clearinghouse of all HPV vaccine technologies available for licensing

• -Patent owners should list patent filings in all jurisdictions, existing licensees (if any), and licensing terms

Coordinate resources for patent landscaping and Freedom to Operate analyses for DCVMs to evaluate potential IP barriers

• -Resources can be coordinated by the WHO IVR and the DCVMN
• -
  Resource provides:

  • ○
    Access to proprietary patent databases when needed
  • ○
    FTO as a service for affordable fee
  • ○
    Scientific and legal expertise to enhance DCVMs’ in-house FTO capacity

Create an HPV technology transfer program

• -Universities, the NIH, and non-profits (i.e. BGMF) should explore the feasibility of a public-private transfer partnership for disseminating novel HPV vaccine technologies
• -Include provisions for access to biological materials, know-how, and clinical data necessary for vaccine development and conducting safety and efficacy trials

Universities should pursue licensing policies that comply with Point 9 of “Nine Points”

• -Consider not patenting in LMCs, or ensuring FTO for manufacturers who make vaccines for LMC markets by employing geographical restrictions on exclusive licenses
• -Mandate that licensees have a plan for access in resource-poor regions, or that they refrain from blocking manufacturing for such regions (i.e. India) and sale in such LMCs.