The end of patent extensions and the Productive Development Partnerships: effects on access to medicines in Brazil

Lopes, Luciana de Melo Nunes; Andrade, Eli Iola Gurgel de; Borde, Elis Mina Seraya

doi:10.1590/S0104-12902024220461en

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Original articles • Saude soc. 33 (1) • 2024 • https://doi.org/10.1590/S0104-12902024220461en copy

The end of patent extensions and the Productive Development Partnerships: effects on access to medicines in Brazil

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

The COVID-19 pandemic has shed light on the negative impact of intellectual property on health and has given new relevance to the Direct Action of Unconstitutionality 5529/DF, which was ruled by the Supreme Court in 2021, resulting in the extinction of automatic patent extensions in Brazil. This documentary case study analyzes the effects of the judicial decision on patent applications and patents of interest for Productive Development Partnerships (PDP), investigating the progress of 90 patent applications related to 15 PDPs drugs of interest until Decembre 31, 2020. Variables for comparing the drug patent scenario with that of the PDPs were researched on the websites of the National Institute of Industrial Property, the Ministry of Health, ANVISA, and the Brazilian Medicines Market Regulation Chamber. Of 88 valid applications, 28 patents were granted, 17 of which had been extended to more than 20 years (24 years and 09 months average). The court decision resulted in a loss of over 68 years of monopoly, potentially opening alternatives for generic production. This resumption of the PDP policy should incorporate strategies to overcome patent barriers.

Keywords:
Access to Essential Medicines and Health Technologies; Intellectual Property of Pharmaceutic Products and Process; Health Economic-Industrial Complex; Health Policy

Drugs (active ingredient)	Therapeutic Class	Patent applications listed in the technical note
glatiramer acetate	immunomodulator	PI 0515033-7; PI 9507758-8
adalimumab	anti-inflammatory; antirheumatic	PI 0315597-8; PI 0415373-1; PI 0520880-7; PI 0512554-5; PI 0615026-8; PI 0618085-0; PI 0717335-0; BR 11 2013 029367 0; PI 0819714-8; PI 1014446-3; BR 11 2013 0116994; PI 0920027-4; PI 0920572-1; PI 1012162-5; BR 11 2013 006403 0; BR 11 2013 008738 2; BR 11 2015 004467 0; BR 11 2012 014710 2; BR 11 2014 008730 0; BR 11 2014 021644 4; PI 9707379-2; PI 9715219-6; PI 0509326-0; PI 0206289-5; PI 0709726-3; PI 9715284-6; PI 0312785-0; PI 0313492-0; PI 0512874-9; PI 0713802-4; PI 0716762-8; PI 101446-3; PI 102162-5
bevacizumab	antineoplastic	PI 0307702-0; PI 0513601-6; PI 0516299-8; PI 0720552-0; PI 0817182-3; PI 0916138-4; BR1120120130935; PI 0313492-0; PI 9816306-0; PI 9816350-7; PI 9809387-8; PI 0411200-8; PI 0412798-6
budesonide, formoterol fumarate dihydrate	antiasthmatic	PI 0307193-6
sevelamer hydrochloride	other products not included in a specific therapeutic class	PI 0015061-4
clozapine	neuroleptic	PI 9811803-0
pramipexole dihydrochloride	antiparkinsonian	PI 0513847-7; PI 0520875-0; PI 0513846-9; PI 0312960-8; PP 1100678-1
everolimus	immunosuppressive agent	PI 0618808-7; PI 0212922-1; PI 9609537-7 PI 9915986-4; PP 1100353-7
infliximab	anti-inflammatory	PI 0113110-9
lopinavir, ritonavir	antiviral (inhibits viral replication)	lopinavir, ritonavir: PI 0413882-1
		lopinavir: PP 1100661-7; PP 1100397-9; PP 1101190-4; PI 0011864-8
		ritonavir: PI 9714310-3; PI 9715203-0
imatinib mesylate	antineoplastic	PI 0309528-2; PI 0307529-0; PI 0608605-5; PI 0812442-6; PI 9810920-0; PI 9816198-9; PI 9816299-3; PI 0114870-2
raltegravir potassium	antiviral	PI 0213522-1; PI 0518760-5
sirolimus	immunosuppressive agent	PI 0412404-9; PP 1100818-0; PP 1100753-2; PP 1100594-7; PI 9403946-1; PI 9403948-8
atazanavir sulfate	antiviral (inhibits viral replication)	PI 0509595-6; PI 9701877-5; PI 9814736-6; PI 0413882-1
trastuzumab	antineoplastic agent; monoclonal antibody	PI 0415448-7; PI 0410260-6

Medication	Patent holder	Patent application number (*mailbox or pipeline)	Application date	Patent grant date	Expiration date of the patent when granted	Date of entry into the public domain	Time between application and maturity (years, months)	Time between application and public domain	Patent expiration date after ADI 5529/DF	Monopoly time lost after ADI 5529/DF (years, months)
GLATIRAMER ACETATE	YEDA RESEARCH AND DEVELOPMENT CO., LTD.(IL)	*PI 9507758-8 (sub judice)	05/23/1995	11/26/2019	05/23/2015	05/23/2015	20.0	20.0	Not applicable (patent terminated)	Not applicable (patent terminated)
ADALIMUMAB	ABBVIE BIOTECHNOLOGY LTD.(BM)	PI 0512554-5	06/23/2005	02/06/2018	02/05/2028	08/06/2019	22.7	14.1	Not applicable (patent terminated)	Not applicable (patent terminated)
ADALIMUMAB	ABBVIE BIOTECHNOLOGY LTD.(BM)	BR 112013011699 4	11/11/2011	04/24/2019	11/11/2031	11/11/2031	20.0	20.0	11/11/2031	0
ADALIMUMAB	ABBVIE BAHAMAS LTD.(US)	BR 112013008738 2	10/11/2011	12/19/2017	10/11/2031	10/11/2031	20.0	20.0	10/11/2031	0
ADALIMUMAB	ABBVIE BIOTECHNOLOGY LTD.(BM)	*PI 9707379-2	02/10/1997	11/03/2009	10/19/2017	10/19/2017	20.8	20.8	Not applicable (patent terminated)	Not applicable (patent terminated)
ADALIMUMAB	ABBVIE BIOTECHNOLOGY LTD.(BM)	*PI 9715219-6	02/10/1997	10/23/2010	10/19/2017	10/19/2017	20.8	20.8	Not applicable (patent terminated)	Not applicable (patent terminated)
BEVACIZUMAB	Chugai Seiyaku Kabushiki Kaisha (JP)	PI 0307702-0	02/14/2003	02/06/2018	02/06/2028	02/06/2028	24.11	24.11	02/14/2023	4.11
BEVACIZUMAB	Genentech, Inc. (US)	PI 0516299-8	10/19/2005	10/06/2020	10/06/2030	10/06/2030	24.11	24.11	10/19/2025	4.11
BEVACIZUMAB	Genentech, Inc. (US)	PI 9816350-7	04/03/1998	03/10/2020	03/10/2030	03/10/2030	31.11	31.11	04/03/2018	11.11
BEVACIZUMAB	GENENTECH, INC. (US)	PI 9809387-8 (sub judice)	04/03/1998	11/22/2016	11/22/26	11/22/26	28.7	28.7	04/03/18	8.7
SEVELAMER HYDROCHLORIDE	Genzyme Corporation (US)	PI 0015061-4	10/13/2000	03/22/2016	03/21/2026	03/21/2026	25.5	25.5	10/13/2020	5.5
CLOZAPINE	Ethyphann (FR)	PI 9811803-0	07/21/1998	07/18/2017	07/17/2027	07/17/2027	28.11	28.11	07/21/2018	8.11
PRAMIPEXOLE DIHYDROCHLORIDE	Dr. Karl Thomae GmbH (DE)	*PP 1100678-1	05/08/1997	10/13/1999	12/22/2004	12/22/2004	7.7	7.7	Not applicable (patent terminated)	Not applicable (patent terminated)
EVEROLIMUS	Novartis AG (CH)	PI 0212922-1	09/27/2002	03/13/2018	03/12/2018	11/02/2019	25.5	17.1	Not applicable (patent terminated)	Not applicable (patent terminated)
EVEROLIMUS	Novartis AG (Novartis SA) (Novartis INC.) (CH)	*PP 1100353-7	04/24/1997	06/06/2000	10/09/2012	09/24/2013	15.5	16.5	Not applicable (patent terminated)	Not applicable (patent terminated)
INFLIXIMAB	JOHNSON & JOHNSON (US)	PI 0113110-9	08/07/2001	03/20/2018	03/19/2028	03/19/2028	26.7	26.7	08/07/2021	6.7
LOPINAVIR	ABBVIE INC. (US)	*PP 1100661-7	05/07/1997	04/11/2000	03/20/2017	03/20/2017	19.10	19.10	Not applicable (patent terminated)	Not applicable (patent terminated)
LOPINAVIR	ABBVIE INC. (US)	*PP 1100397-9	04/30/1997	04/11/2000	11/21/2016	11/21/2016	19.6	19.6	Not applicable (patent terminated)	Not applicable (patent terminated)
IMATINIB MESYLATE	Novartis AG (CH)	PI 0307529-0	02/06/2003	01/30/2018	01/29/2028	03/14/2020	24.11	17.1	Not applicable (patent terminated)	Not applicable (patent terminated)
IMATINIB MESYLATE	Novartis AG (CH)	PI 0114870-2 (sub judice)	10/26/2001	06/16/2020	06/15/2030	06/15/2030	28.7	28.7	10/26/2021	8.7
RALTEGRAVIR POTASSIUM	Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. (IT)	PI 0213522-1	10/21/2002	06/13/2017	06/12/2027	06/12/2027	24.7	24.7	10/21/2022	4.7
RITONAVIR	ABBVIE INC (US)	PI 9714310-3	11/12/1997	02/18/2003	11/12/2017	05/29/2018	20.0	20.6	Not applicable (patent annulled)	Not applicable (patent annulled)
RITONAVIR	ABBVIE INC. (US)	PI 9715203-0	11/12/1997	03/05/2003	11/12/2017	11/12/2017	20.0	20.0	Not applicable (patent terminated)	Not applicable (patent terminated)
SIROLIMUS	Wyeth (US)	*PP 1100818-0	05/12/1997	07/13/1999	09/30/2013	01/28/2017	16.4	19.8	Not applicable (patent terminated)	Not applicable (patent terminated)
SIROLIMUS	Wyeth (US)	*PP 1100753-2	05/12/1997	07/13/1999	09/30/2013	09/30/2013	16.4	16.4	Not applicable (patent terminated)	Not applicable (patent terminated)
SIROLIMUS	Solvay Pharmaceuticals GmbH (DE)	*PP 1100594-7	05/13/1997	06/15/1999	09/18/2002	09/18/2002	5.4	5.4	Not applicable (patent terminated)	Not applicable (patent terminated)
ATATAZANAVIR SULFATE	Novartis AG (Novartis SA) (Novartis Inc.) (CH)	*PI 9701877-5	04/22/1997	09/28/2004	04/22/2017	04/22/2017	20.0	20.0	Not applicable (patent terminated)	Not applicable (patent terminated)
ATATAZANAVIR SULFATE	Bristo1-Myers Squibb Company (US)	PI 0509595-6	05/03/2005	05/14/2019	05/13/2029	05/13/2029	24.0	24.0	05/03/2025	4

Drug	PDP phase in 09/2020	% of demand to be achieved	Official Pharmaceutical Laboratory	National private partner	International private partner	Private entity - active pharmaceutical ingredient (API)	Is there a generic registered with ANVISA?	Patent scenario:	Observation
GLATIRAMER ACETATE	II	100	FURP	Cristália Produtos Químicos Farmacêuticos Ltda.	-	Cristália Produtos Químicos Farmacêuticos Ltda.	No	There is a mailbox patent whose termination is being challenged in court. As of December 31, 2020, the analysis of PI 0515033-7 had not been completed.	The analysis of PI 0515033-7 had not been completed even after prioritized examination was granted in 2017. In 2015, Cristália submitted a subsidy for the examination, indicating its interest in the request to carry out local production. If the rejection were reversed and a patent was granted, it would be in force until 2025, six years less than before ADI 5529.
ADALIMUMAB	II	40	Bio-manguinhos	Bionovis S.A - Companhia Brasileira de Biotecnologia Farmacêutica	-	Bionovis S.A - Companhia Brasileira de Biotecnologia Farmacêutica	No	There are two terminated mailbox product patents. But there are two patents, apparently process patents, in force until 2031.	The mailbox patents were originally to run until 2019 and 2020, but the INPI questioned their extension under the sole paragraph of article 40 on the grounds that it was not a regular patent. Even at an early stage, the announcement of the adalimumab PDP resulted in extrajudicial notices being sent by Abbvie in 2015 and 2016 to those involved in the PDP. One of the patents in force had its application refusal by ANVISA reversed by a court order.
	II (suspended)	10	Butantan	Libbs Farmacêutica Ltda.	-	Libbs Farmacêutica Ltda.	No
	II	20	Butantan	Libbs Farmacêutica Ltda.	-	Libbs Farmacêutica Ltda.	No
	II (suspended)	30	TECPAR	Orygen Biotecnologia S/A	Pfizer Incorporated	Orygen Biotecnologia S/A	No
BEVACIZUMAB	II (suspended)	25	Bio-manguinhos	Bionovis S.A - Companhia Brasileira de Biotecnologia Farmacêutica	-	Bionovis S.A - Companhia Brasileira de Biotecnologia Farmacêutica	No	Two patents that apparently protect the drug were immediately terminated after the judgment of ADI 5529/DF. There are two other patents in force, apparently process patents, which had their validity period reduced by almost 5 years each, but remain in force until 2023 and 2025. There is also an unfinished application.	The terminated product patents would have been in force until 2026 and 2031 if ADI 5529/DF had not been judged. Patent 9809387-8 had its application refusal by ANVISA reversed by a court order, and its granting was being challenged in court by Libbs, which requested for the patent to be invalidated. The unfinished application, apparently in process, was granted prioritized examination in 2019 and is awaiting analysis of the appeal against the rejection.
	II	25	Butantan	Libbs Farmacêutica Ltda.	-	Libbs Farmacêutica Ltda.	No
	II (suspended)	50	TECPAR	Orygen Biotecnologia S/A	Pfizer Incorporated	Orygen Biotecnologia S/A	No
SEVELAMER HYDROCHLORIDE	III	50	Farmanguinhos	Cristália Produtos Químicos Farmacêuticos Ltda.	-	ITF Chemical Ltda.	Yes	There seems to be no patent protecting the drug in Brazil. A process patent was terminated by ADI 5529/DF.	The process patent would have been in force for 25 years and 5 months if ADI 5529/DF had not been judged.
SEVELAMER HYDROCHLORIDE	IV (suspended)	50	Bahiafarma	Cristália Produtos Químicos Farmacêuticos Ltda.	-	ITF Chemical Ltda.	Yes
CLOZAPINE	IV	100	LAFEPE	Cristália Produtos Químicos Farmacêuticos Ltda.	-	Cristália Produtos Químicos Farmacêuticos Ltda.	Yes	There seems to be no patent protecting the drug. A patent, apparently a process patent, was terminatedby ADI 5529/DF.	The process patent was granted by reversing a previous rejection by the INPI and was meant to be in force for 28 years and 11 months, prior to the judgment of ADI 5529/DF.
PRAMIPEXOLE DIHYDROCHLORIDE	III	50	Farmanguinhos	Nortec Química S/A	Boehringer Ingelheim do Brasil Química e Farmacêutica Ltda.	Nortec Química S/A	Yes	There seems to be no patent protecting the drug. A pipeline product patent was terminated in 2004. Other applications were rejected or archived.	The holder of the pipeline patent tried to extend its term in court. All the other applications received an opinion from ANVISA against the granting of the patent. Eurofarma submitted a subsidy for the examination of several applications.
EVEROLIMUS	II (suspended)	50	Farmanguinhos	-	-	-	No	There seems to be no patent in force protecting the drug. Pipeline product patent terminated in 2013. Process patent terminated in 2019.	The rejection of another patent application was challenged in court, but Novartis lost. The company was a partner in the PDP, whose term of commitment was signed in 2012, but went out of business in 2015. The terms of commitment of the PDPs with Farmanguinhos and NUPLAM are from 2018.
EVEROLIMUS	II	50	NUPLAM	EMS S/A		Nortec Química S/A	No
INFLIXIMAB	II (suspended)	50	TECPAR	Orygen Biotecnologia S/A	Pfizer Incorporated	Orygen Biotecnologia S/A	No	There seems to be no patent protecting the drug. A patent lost 6 years and 7 months of validity after the judgment of ADI 5529/DF and was terminated in August 2021.	The patent was granted contrary to the subsidy for examination by ANVISA. EMS submitted various subsidies for the technical examination of the patent application.
INFLIXIMAB	III	50	Bio-manguinhos	Bionovis S.A. - Companhia Brasileira de Biotecnologia Farmacêutica	Janssen-Cilag Farmacêutica Ltda.	Bionovis S.A. - Companhia Brasileira de Biotecnologia Farmacêutica	Yes
IMATINIB MESYLATE	IV	50	Farmanguinhos	Cristália Produtos Químicos Farmacêuticos Ltda.	-	Cristália Produtos Químicos Farmacêuticos Ltda.	Yes	Pipeline patent PP 1100739-7 (not included in the study), which protects the drug, terminated since 2012. A patent that could apparently affect the production of generics had its validity reduced by 8 years and 7 months after the judgment of ADI 5529/DF and was terminated in October 2021.	The patent that was terminated in October 2021 was “sub judice,” and its nullity was demanded in court by several generic pharmaceutical companies. An opinion from ANVISA was submitted as a subsidy to the examination by the INPI and went against the granting of the patent.
IMATINIB MESYLATE	IV	50	IVB	Laborvida EMS S/A	-	Globe Química S/A	Yes
ATATAZANAVIR SULFATE	III	100	Farmanguinhos	Nortec Química S/A	Bristol-Myers Squibb Company (BMS)	Nortec Química S/A	Yes	The patent protecting the product was terminated in 2017. A granted process patent had its validity reduced by 4 years by ADI 5529/DF, but will remain in force until 2025.	The process patent was granted contrary to the subsidy for examination by ANVISA. The terminated product patent belonged to Novartis and was licensed to Bristol-Myers Squibb, which holds the current process patent. To establish the PDP, a voluntary license agreement was signed with BMS in 2011.
TRASTUZUMAB	II	40	Bio-manguinhos	Bionovis S.A. - Companhia Brasileira de Biotecnologia Farmacêutica	-	Bionovis S.A. - Companhia Brasileira de Biotecnologia Farmacêutica	Yes	There seems to be no patent protecting the drug. A pipeline patent (PP1101137-8, not included in the technical note) was terminated in 2014.	The applications were rejected, in accordance with the examination subsidy presented by ANVISA. Several other applications were mentioned in other studies, but there is no clarity on the main patent that protected the product. Roche has been a partner in the PDP since 2017, which may indicate the use of the PDP as a monopoly extension. Moreover, there was an investigation by the TCU and the MPF into the overpricing of the generic produced by TECPAR.
	II (suspended)	20	Butantan	Libbs Farmacêutica Ltda.	-	Libbs Farmacêutica Ltda.	No
	III (suspended)	40	TECPAR	Axis Biotec Empreendimentos e Participações Ltda	F. Hoffmann-La Roche Ltd.	Axis Biotec Empreendimentos e Participações Ltda	Yes

Faculdade de Saúde Pública, Universidade de São Paulo. Associação Paulista de Saúde Pública. Av. dr. Arnaldo, 715, Prédio da Biblioteca, 2º andar sala 2, 01246-904 São Paulo - SP - Brasil, Tel./Fax: +55 11 3061-7880 - São Paulo - SP - Brazil
E-mail: saudesoc@usp.br

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[1] Correspondence Luciana de Melo Nunes Lopes Av. Professor Alfredo Balena, 190. Belo Horizonte, MG, Brasil. CEP: 31270-901