Prior Art Listing

Below is a comprehensive list of all prior art documents which were raised for the Sanofi 1, Sanofi 2 and Yellow Fever applications along with a brief description of each.

Prior Art for Sanofi 1 (Patent Application no. BR 11 2015 001145-4)

D1 – WO2003101397

Date of Publishing: 11/12/2003

Published as: WIPO International Patent Application

    Main Disclosures:
  • Tetravalent Dengue Vaccines which induces immunty against all four Dengue Virus serotypes (DEN 1-4)
  • Describes the development of CYD, i.e., chimeric yellow fever/dengue (CYD) constructs comprising a yellow fever backbone, in which the pre-membrane (prM) and envelope (E) genes of wild-type dengue viruses are inserted. For each dengue serotype, a chimera was generated (CYD1-4, also referred to as ChimerivaxTM dengue serotype 1-4) for application in the tetravalent vaccine composition
  • The wild type dengue viruses from which the chimeric viruses have been derived are the same as of the ones disclosed in Example 1 of application BR112015001145-4.

D2 – Guy et al.

Date of Publishing: 01/09/2010

Published as: Scientific Article in the “Human Vaccines” journal, v. 6, issue 9, p. 696-705.

    Main Disclosures:
  • The review is concerned about developments made in relation to Sanofi Pasteur tetravalent vaccine candidate composed of four recombinant live attenuated vaccines based on a yellow fever vaccine 17D (YFV 17D) backbone, each expressing the prM and envelope genes of one of the four dengue virus serotypes, also known as Chimerivax.
  • The paper discusses about the overall development of the CYD 1-4 viruses used in the relevant vaccine, i.e., the chimeric yellow fever/dengue (CYD) constructs (see Figure 1); and comments about the Pre-clinical evaluation and Clinical Development of the vaccine, at the occasion.
  • Phase I studies with monovalent CYD-2 and Tetravalent (TDV) vaccine have been discussed in this Review, with seroconversion of volunteers being shown, inclusive for all four serotypes with TDV.
  • Phase IIb and Phase III clinical evaluations being conducted are mentioned in the paper, thus showing that efficacy tests were being carried out with the vaccine. Particularly, the Phase IIb Trial being conducted in Thailand (endemic area) with children aged 4-11 years, which results are described in application BR112015001145-4 (Example 1), are reported in this paper.
  • The document, therefore, discloses the immunogenicity achieved with the TDV vaccine, the use of the vaccine in humans (children from endemic areas), and the dosage regimen of 0-6-12 months.

D3 – Study NCT01373281, CYD, sponsored by Sanofi

Date of Publishing: 14/06/2011

Published as: Study of a Novel Tetravalent Dengue Vaccine in Healthy Children Aged 2 to 14 Years in Asia

    Main Disclosures:
  • The clinical trial is a Phase III study with CYD-TDV (or Chimerivax) vaccine, in particular a clinical trial concerned with efficacy of the CYD-TDV vaccine in preventing symptomatic, virologically confirmed dengue cases due to any of the four Dengue Virus serotype.
  • The CYD-TDV dengue vaccine is applied to children aged 2 to 14 years.
  • The vaccination regimen corresponds to 3 vaccinations at 0, 6 and 12 months.
  • This document corroborates the vaccination regimen described in Guy et al., 2010 and in Example 1 from application BR112015001145-4.
  • This study is commented by Capeding et al., 2014, Lancet 384:1358-65

D4 – Study NCT01374516, CYD, sponsored by Sanofi

Date of Publishing: 16/06/2011

Published as: Study of a Novel Tetravalent Dengue Vaccine in Healthy Children and Adolescents Aged 9 to 16 Years in Latin America

    Main Disclosures:
  • The clinical trial is directed to a Phase III study regarding the vaccine TDV-CYD, in particular, like D4, to a clinical trial concerned with efficacy (conference of protection) of the TDV-CYD vaccine against dengue disease.
  • The CYD dengue vaccine is applied to children aged 9 to 16 years in Latin America.
  • The vaccination regimen corresponds to 3 vaccinations at 0, 6 and 12 months.
  • This document corroborates the vaccination regimen described in Guy et al., 2010 and in Example 1 from application BR112015001145-4.
  • This study is commented by Villar et al., 2015, N Engl J Med 372:113-23

D5 – WO2006134443 – DENGUE SEROTYPE 2 ATTENUATED STRAIN

Date of Publishing: 21/12/2006

Published as: WIPO International Patent Application

    Main Disclosures:
  • The application discloses a live attenuated VDV2 strain derived from dengue 2 strain PDK53-16681 (also known as LAV-2). The tetravalent vaccine VDV-2/CYD-1,3,4 is also foreseen in the document.
  • VDV2 amino acid and nucleotide sequences, also compared to PDK53-16681, are revealed in the application (below).
  • The full sequence of VDV-2 is disclosed as SEQ ID NO: 1 in this application.
  • The tetravalent vaccine VDV-2/CYD-1,3,4 was object of a Phase II Clinical Trial registered with number NCT00740155 (first posted on August 22, 2008) to provide safety information concerning the tested bivalent and tetravalent formulations.
  • Health Naïve Volunteers aged 18 to 45 years participated from this study.

D6 – Osorio et al.

Date of Publishing: 21/07/2011

Published as: Scientific Article in the “Vaccine” journal, v. 29, issue 42, p. 7251-7260.

    Main Disclosures:
  • This document consists of a review article disclosing the results of a chimeric dengue-2 PDK-53-based tetravalent vaccine successfully protecting monkeys in challenge studies. PDK-53 strain is also known as LAV-2, the same serotype 2 strain disclosed in Examples 2 and 3 from application BR112015001145-4, from which VDV-2 strain, employed in Example 4 has been attenuated.
  • The paper describes the attenuated DEN-2 PDK-53 strain and chimeric viruses containing the prM and E genes from DEN-1, DEN-3 and DEN-4, in a DEN-2 PDK-53 backbone, known as DENVax.
  • The tetravalent vaccine candidate showed a safety profile and immunogenicity against the four Dengue serotypes, as shown in Phase I Clinical Trials.
  • This document anticipates the use of the serotype-2 Dengue virus strain LAV-2 (PDK-53), both in the attenuated form and in the chimeric form.

D7 – Bhamarapravati & Sutee

Date of Publishing: 28/03/2000; Date of Publishing (online): 01/09/2010

Published as: Scientific article in the “Vaccine” journal, v. 18, p. 44-47.

    Main Disclosures:
  • Bhamarapravati is a short communication reporting the developments of dengue vaccines, at the Mahidol University group based on live attenuated (non-chimeric) dengue viruses obtained by serial passages of the viruses in primary dog kidney cells or primary African green monkey kidney cells.
  • According to the authors, tetravalent vaccines described have been tested in Thai volunteers, and were found to be immunogenic in both adults and children.
  • This document is relevant with regard to the broad component “live attenuated dengue virus” from currently pending claim 1.

Prior Art for Sanofi 2 (Patent Application no. BR 11 2017 004197-9)

D1 – WO2014016362

Date of Publishing: 30/01/2014

Published as: WIPO International Patent Application

    Main Disclosures:
  • The disclosed invention relates to a dengue virus serotype 2 vaccine composition.
  • The patent application describes the results of a Phase IIb clinical Trial conducted by the Applicant, as disclosed in the application as Example 1.
  • Strains are selected to compose the prME component of the vaccine against the Dengue caused by serotype 2 Dengue virus based on a Global Consensus Sequence obtained in Example 2: LAV-2 (PDK53-16681); BID-V585; PR/DB023; and MD-1280.
  • Tetravalent vaccines are also foreseen in the application.
  • Tests with a tetravalent vaccine Chimerivax (CYD-TDV) compared to other Test Tetravalent Formulations in which component of Serotype 2 is varied, are reported.
  • Examples 4 and 5 describe comparative tests in Cynomolgus monkeys and naïve adults in Mexico to assess the immunogenicity against DEN-2 for the tested formulations compared to the Chimerivax (CYD-TDV), respectively.

D2 – WO2014016360

Date of Publishing: 30/01/2014

Published as: WIPO International Patent Application

    Main Disclosures:
  • The disclosed invention relates to a tetravalent vaccine composition against Dengue.
  • This a patent application describes the results of a Phase IIb clinical Trial conducted by the Applicant, as disclosed in the application as Example 1.
  • Due to an alleged lack of efficacy of the Chimerivax (CYD-TDV) vaccine against DEN-2, like in the WO2014/016362 (D1), a Global Consensus Sequence was developed, and DEN-2 Dengue virus strains have been selected (Example 2), namely: BID-V585; MD-1280; LAV-2 (PDK53-16681); and PR/DB023
  • In Example 3, construction of the cDNA clones corresponding to the optimized serotype 2 chimeric viruses selected in Example 2 is described. The virus used as backbone for the constructions is the Yellow Fever strain YF17D204, using Chimerivax technology. No tests with these chimeric strains are reported in this document.
  • Example 4 corresponds to the immunogenicity test of CYD 1, 2 and 4-VDV2 composition in Naïve adults in Mexico. This Example is identical to Example 5 from WO2014016362 (D1).

D3 – Bhamarapravati & Sutee

Date of Publishing: 28/03/2000; Date of Publishing (online): 01/09/2010

Published as: Scientific article in the “Vaccine” journal, v. 18, p. 44-47.

    Main Disclosures:
  • Bhamarapravati is a short communication reporting the developments of dengue vaccines, at the Mahidol University group based on live attenuated (non-chimeric) dengue viruses obtained by serial passages of the viruses in primary dog kidney cells or primary African green monkey kidney cells.
  • According to the authors, tetravalent vaccines described have been tested in Thai volunteers, and were found to be immunogenic in both adults and children.
  • This document is relevant with regard to the broad component “live attenuated dengue virus” from currently pending claim 1.

D4 – Guy et al.

Date of Publishing: 01/09/2010

Published as: Scientific Article in the “Human Vaccines” journal, v. 6, issue 9, p. 696-705.

    Main Disclosures:
  • The review is concerned about developments made in relation to Sanofi Pasteur tetravalent vaccine candidate composed of four recombinant live attenuated vaccines based on a yellow fever vaccine 17D (YFV 17D) backbone, each expressing the prM and envelope genes of one of the four dengue virus serotypes, also known as Chimerivax.
  • The paper discusses about the overall development of the CYD 1-4 viruses used in the relevant vaccine, i.e., the chimeric yellow fever/dengue (CYD) constructs (see Figure 1); and comments about the Pre-clinical evaluation and Clinical Development of the vaccine, at the occasion. The vaccine composition in this document is the same being tested in application BR112017004197-9 .
  • Phase I studies with monovalent CYD-2 and Tetravalent (TDV) vaccine have been discussed in this Review, with seroconversion of volunteers being shown, inclusive for all four serotypes with CYD-TDV (Chimerivax).
  • Phase IIb and Phase III clinical evaluations being conducted are mentioned in the paper, thus showing that efficacy tests were being carried out with the vaccine, at the occasion. The phase III trial in children and adolescents in Latin America (Example 1) and Asia (Example 2) are mentioned herein. The phase IIb study from Sanofi 1, and included in the Example 4 (LTFU) of the instant application are also reported.
  • The document, therefore, discloses the immunogenicity achieved with the TDV vaccine, the use of the vaccine in humans (children from endemic areas), and the dosage regimen of 0-6-12 months.

D5 – Osorio et al.

Date of Publishing: 21/07/2011

Published as: Scientific Article in the “Vaccine” journal, v. 29, issue 42, p. 7251-7260.

    Main Disclosures:
  • This document consists of a review article disclosing the results of a chimeric dengue-2 PDK-53-based tetravalent vaccine successfully protecting monkeys in challenge studies.
  • The paper describes the attenuated DEN-2 PDK-53 strain and chimeric viruses containing the prM and E genes from DEN-1, DEN-3 and DEN-4, in a DEN-2 PDK-53 backbone, known as DENVax.
  • The tetravalent vaccine candidate showed a safety profile and immunogenicity against the four Dengue serotypes, as shown in Phase I Clinical Trials.
  • This document is relevant with respect to the broad component “live attenuated chimeric dengue virus” from currently pending claim 1.

Prior Art for Yellow Fever (Patent Application no. BR 11 2017 028212-7)

D1 – Stamaril™ summary of product characteristics

Published as: Summary of Product Characteristics – Sanofi Pasteur (Last Update:15/02/2021)

Name of the medicinal product

  • STAMARIL, powder and solvent for suspension for injection in pre-filled syringe.
  • Yellow fever vaccine (Live).

    Qualitative and quantitative composition

  • After reconstitution, 1 dose (0.5 mL) contains: Yellow fever virus1 17D-204 strain (live, attenuated)……………………………………….not less than 1000 IU

    1 produced in specified pathogen-free chick embryos Excipients with known effects:

    This product contains approximately 8 mg of sorbitol (E420) per dose. For the full list of excipients, see Section 6.1.

    • D2 – YF-Vax™ leaflet

    Published as: Package Insert – YF-Vax

    DESCRIPTION

    YF-VAX®, Yellow Fever Vaccine, for subcutaneous use, is prepared by culturing the 17D-204 strain of yellow fever virus in living avian leukosis virus-free (ALV-free) chicken embryos. The vaccine contains sorbitol and gelatin as a stabilizer, is lyophilized, and is hermetically sealed under nitrogen. No preservative is added. Each vial of vaccine is supplied with a separate vial of sterile diluent, which contains Sodium Chloride Injection USP – without a preservative. YF-VAX is formulated to contain not less than 4.74 log10 plaque forming units (PFU) per 0.5 mL dose throughout the life of the product. Before reconstitution, YF-VAX is a pinkish color. After reconstitution, YF-VAX is a slight pink-brown suspension.

    The vial stoppers for YF-VAX and diluent are not made with natural rubber latex

    D3 – Dengvaxia ™ summary of product characteristics

    Published as: Summary of Product Characteristics – Sanofi Pasteur

    1. NAME OF THE MEDICINAL PRODUCT

    Dengvaxia, powder and solvent for suspension for injection in pre-filled syringe
    dengue tetravalent vaccine (live, attenuated)

    2. QUALITATIVE AND QUANTITATIVE COMPOSITION

    After reconstitution, one dose (0.5 mL) contains:

    Chimeric yellow fever dengue virus serotype 1 (live, attenuated)*……….. 4.5 – 6.0 log10 CCID50/dose**
    Chimeric yellow fever dengue virus serotype 2 (live, attenuated)*……….. 4.5 – 6.0 log10 CCID50/dose**
    Chimeric yellow fever dengue virus serotype 3 (live, attenuated)*……….. 4.5 – 6.0 log10 CCID50/dose**
    Chimeric yellow fever dengue virus serotype 4 (live, attenuated)*……….. 4.5 – 6.0 log10 CCID50/dose**

    *Produced in Vero cells by recombinant DNA technology. This product contains genetically modified organisms (GMOs).
    **CCID50: 50% Cell Culture Infectious Dose.

    D4 – CYD 29 Clinical trial protocol (US)

    Date of Publishing: 19/09/ 2011

    Published as: Study of Yellow Fever Vaccine Administered With Tetravalent Dengue Vaccine in Healthy Toddlers (NCT01436396)

      Main Disclosures:
    • Corresponds to protocol of Example 1.
    • The CYD dengue vaccine is applied to children aged 9 to 16 years in Latin America.
    • The clinical trial is a Phase III study with Chimerivax. Primary objective is to demonstrate non-inferiority of the immune response against YF in flavivirus naïve subjects at baseline receiving one dose of Stamaril™ concomitantly with the 1st dose of CYD-TDV compared to subjects receiving one dose of Stamaril ™vaccine concomitantly with placebo.
    • Stamaril™ applied together with the 1st dose of Chimerivax at M0, 3 doses applied at a 6-month intervals
    • This document anticipates Example 1 from “YF” application.

    D5 – CYD51 Clinical trial protocol (US)

    Date of Publishing: 8/12/2011

    Published as: Immune Response to Different Schedules of a Tetravalent Dengue Vaccine Given With or Without Yellow Fever Vaccine (NCT01488890)

    D6 – EU Clinical trials register, CYD29, sponsored by Sanofi

    Date of Publishing: 08/02/2016

    Published as: Study of Yellow Fever Vaccine Administered With Tetravalent Dengue Vaccine in Healthy Toddlers (NCT01436396)

      Main Disclosures:
    • It may considered as prior art in BR for the feature not disclosed by priority (within the priority discussion) (if the claims are amended to co-administration for protective response against YF AND neutralizing antibodies against each of the 4 DENV serotypes).
    • This document anticipates all results of Example 1 from “YF” application.
    • The clinical trial is a Phase III study with Chimerivax + Stamaril in toddlers.

    D7 – PI0614265-6 (Acambis, Inc. & Sanofi Pasteur)

    Date of Publishing: 22/02/2007

    Published as: Brazilian Patent Application

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