“The rationale for the fixed combination of efavirenz, emtricitabine and tenofovir DF is to simplify HIV-treatment regimens and to improve adherence to therapy by providing combination antiretroviral therapy for administration as a single, once-daily tablet. The individual active substances are already approved to be used together in combination therapy of HIV-1 infected patients.”
“[3] Medicinal products, especially those that are the result of long, costly research will not continue to be developed in the Community and in Europe unless they are covered by favourable rules that provide for sufficient protection to encourage such research. [4] At the moment the period that elapses between the filing of an application for a patent for a new medicinal product and authorisation to place the medicinal product on the market makes the period of effective protection under the patent insufficient to cover the investment put into the research. [5] This situation leads to a lack of protection which penalises pharmaceutical research. [6] There exists a risk of research centres situated in the Member States relocating to countries that offer greater protection. [7] A uniform solution at Community level should be provided for, thereby preventing the heterogeneous development of national laws leading to further disparities which would be likely to create obstacles to the free movement of medicinal products within the Community and thus directly affect the establishment and the functioning of the internal market. [8] Therefore, the creation of a supplementary protection certificate granted, under the same conditions, by each of the Member States at the request of the holder of a national or European patent relating to a medicinal product for which marketing authorisation has been granted is necessary. A Regulation is therefore the most appropriate legal instrument.”
“Article 1 Definitions For the purpose of this Regulation: (a) ‘medicinal product’ means any substance or combination of substances presented for treating or preventing disease in human beings or animals and any substance or combination of substances which may be administered to human beings or animals with a view to making a medical diagnosis or to restoring, correcting or modifying physiological functions in humans or in animals; (b) ‘product’ means the active ingredient or combination of active ingredients of a medicinal product; (c) ‘basic patent’ means a patent which protects a product as defined in (b) as such, a process to obtain a product or an application of a product, and which is designated by its holder for the purpose of the procedure for grant of a certificate; … Article 3 Conditions for obtaining a certificate A certificate shall be granted if, in the Member State in which the application referred to in Article 7 is submitted and at the date of that application - (a) the product is protected by a basic patent in force; … (c) the product has not already been the subject of a certificate; … Article 4 Subject-matter of protection Within the limits of the protection conferred by the basic patent, the protection conferred by a certificate shall extend only to the product covered by the authorisation to place the corresponding medicinal product on the market and for any use of the product as a medicinal product that has been authorised before the expiry of the certificate. Article 5 Effects of the certificate Subject to the provisions of Article 4, the certificate shall confer the same rights as conferred by the basic patent and shall be subject to the same limitations and the same obligations.”
“Next, the Court observes that the second sentence of Article 3(2) of Regulation No 1610/96 must be interpreted not solely on the basis of its wording, but also in the light of the overall scheme and objectives of the system of which it is a part (see, by analogy,Case C-292/00 Davidoff[2003] ECR I-389 , paragraph 24).”
“41. Those rules are intended to achieve a balance between the various interests at stake in the pharmaceutical sector. Those interests include, on the one hand, the interests of the undertakings and institutions, some of which pursue very costintensive research in the pharmaceutical sector and therefore favour an extension of the term of protection for their inventions in order to be able to balance out the investment costs. On the other hand, there are the interests of the producers of generic medicines who, as a consequence of the extension of the term of protection of the active ingredients under patent protection, are precluded from producing and marketing generic medicines. It is also relevant in this connection that, in general, the marketing of generic medicinal products has the effect of lowering the prices of the relevant medicinal products. Against that background, the interests of patients lie between the interests of the undertakings and institutions conducting research and those of the producers of generic medicines. That is because patients have an interest, on the one hand, in the development of new active ingredients for medicinal products, but, on the other, they also have an interest in those products then being offered for sale as cheaply as possible. The same applies to State health systems in general which, in addition, have a particular interests in preventing old active ingredients from being brought onto the market in slightly modified form under the protection of certificates but without genuine innovation and thereby artificially driving up expenditure in the health section. 42. Against the background of that complex situation as regards interests, Regulation 1768/92 sought to achieve a balanced solution taking due account of the interests of all parties. In view of the complexity of that balance of interests, it is necessary to proceed with great caution when making a teleological interpretation of the individual provisions of the regulation.”
“35. It occurs very often that one and the same product is successfully granted several authorizations to be placed on the market, namely each time a modification is made affecting the pharmaceutical form, dose, composition, indications, etc. In such a case, only the first authorization for the product to be placed on the market, in the Member State in which the application is presented is taken into account for the purposes of the proposal for a Regulation, in particular for calculating the period of six months which the holder of the basic patent has to submit an application for a certificate. Furthermore, if the first authorization given is also the first authorization to place the product on the market in the Community, it serves as the only reference for all of the Member States for the purpose of calculating the duration of each of the certificates granted in each of the Member States for the same product (see Article B). 36. Lastly, the product must not have been the subject of a certificate in the Member State concerned. The certificate is designed to encourage research into new medicinal products so that the duration of protection by patent, is sufficient to enable the investments made in the research to be recovered. However, it would not be acceptable in view of the balance required between the interests concerned, for this total duration of protection for one and the same medicinal product to be exceeded. This might nevertheless be the case if one and the same product were able to be the subject of several successive certificates. This calls for a strict definition of the product within the meaning of Article 2. If a certificate has already been granted for the active ingredient itself, a new certificate may not be granted for one and the same active ingredient whatever minor changes may have been made regarding other features of the medicinal product (use of a different salt, different excipients, different pharmaceutical presentation, etc). In conclusion, it should be noted that, although one and the same product may be the subject of several patents and several authorizations to be placed on the market in one and the same Member State, the supplementary protection certificate will only be granted for that product on the basis of a single patent and a single authorization to be placed on the market, namely the first chronologically given in the State concerned (the first authorization in the Community being taken only to calculate a uniform duration of different certificates for one and the same product).”
“26. It must be borne in mind in that regard that the third and fourth recitals in the preamble give as a reason for the adoption of the Regulation the insufficient duration of the effective protection under the patent to cover the investment put into the pharmaceutical research. The Regulation thus seeks to make up for that insufficiency by creating a supplementary protection certificate for medicinal products, which may be obtained by the holder of a national or European patent under the same conditions in each Member State. 27. Article 6 of the Regulation confirms that the certificate is to be granted to the holder of the basic patent or his successor in title. Article 1(c) mentions the basic patents which may be designated for the purpose of the procedure for the grant of a certificate, namely those which protect a product as such, a process to obtain a product or an application of a product. The Regulation thus seeks to confer supplementary protection on the holders of such patents, without instituting any preferential ranking amongst them. 28. Consequently, where a product is protected by a number of basic patents in force, which may belong to a number of patent holders, each of those patents may bedesignated for the purpose of the procedure for the grant of a certificate. Under Article 3(c) of the Regulation, however, only one certificate may be granted for each basic patent.”
“ … where a patent protects a product, in accordance with Article 3(c) of Regulation No 469/2009, only one certificate may be granted for that basic patent (see Biogen, paragraph 28).”
“Does Regulation No 469/2009 …, more particularly Article 3(c) thereof, preclude, in a situation where there is a basic patent in force which protects several products, the holder of the basic patent from being granted a certificate for each of the protected products?”
“In a situation in which multiple products are protected by a basic patent in force, does Regulation [No 469/2009], and in particular Article 3 preclude the proprietor of the patent being issued a certificate for each of the products protected?”
“… it is possible, in principle, on the basis of a patent which protects several different ‘products’, to obtain several SPCs in relation to each of those different products, provided, inter alia, that each of those products is ‘protected’ as such by that ‘basic patent’ within the meaning of Article 3(a) of Regulation No 469/2009, in conjunction with Article 1(b) and (c) of that regulation …”
“… in circumstances such as those in the main proceedings, in which, on the basis of a patent protecting an innovative active ingredient and an MA for a medicinal product containing that ingredient as the single active ingredient, the holder of that patent has already obtained an SPC for that active ingredient, Article 3(c) of Regulation No 469/2009 must be interpreted as precluding the holder of that patent from obtaining, on the basis of that same patent but an MA for a different medicinal product containing that active ingredient in combination with another active ingredient which is not protected as such by the patent, a second SPC relating to that combination of active ingredients.”
“In the main proceedings, in the light of paragraph 30 above, the combination of the four active ingredients in question (which includes HPV-16) as well as HPV-16 as an active ingredient individually, are protected by Georgetown University’s basic patent within the meaning of Article 3(a) of Regulation No 469/2009. Therefore, Article 3(c) of that regulation does not, in principle, preclude Georgetown University being granted, on the basis of that patent and the same MA, namely the marketing authorisation for Gardasil, an SPC both for the combination of active ingredients (HPV-6, HPV-11, HPV-16 and HPV-18) and for the active ingredient HPV-16 individually. Even if the protection conferred by two such SPCs were to overlap, they would, in principle, expire on the same date.”
“2. For the purposes of determining whether the conditions in Article 3 [of the SPC Regulation] are made out at the date of the application for an SPC for a product comprised of the combination of active ingredients A and B, where: (a) the basic patent in force includes a claim to a product comprising active ingredient A and a further claim to a product comprising the combination of active ingredients A and B, and (b) there is already an SPC for a product comprising active ingredient A (‘Product X’), is it necessary to consider whether the combination of active ingredients A and B is a distinct and separate invention from that of A alone? 3. Where the basic patent in force ‘protects’ pursuant to Article 3(a) [of Regulation No 469/2009]: (a) a product comprising active ingredient A (Product X); and (b) a product comprising a combination of active ingredient A and active ingredient B (‘Product Y’); and where: (c) an authorisation to place Product X on the market as a medicinal product has been granted; (d) an SPC has been granted in respect of Product X; and (e) a separate authorisation to place Product Y on the market as a medicinal product has subsequently been granted, does … Regulation [No 469/2009], in particular Articles 3(c) and (d) and/or 13(1), preclude the proprietor of the patent being issued with an SPC in respect of Product Y? Alternatively, if an SPC can be granted in respect of Product Y, should its duration be assessed by reference to the grant of the authorisation for Product X or the authorisation for Product Y?” (a) the basic patent in force includes a claim to a product comprising active ingredient A and a further claim to a product comprising the combination of active ingredients A and B, and (b) there is already an SPC for a product comprising active ingredient A (‘Product X’), is it necessary to consider whether the combination of active ingredients A and B is a distinct and separate invention from that of A alone? (a) a product comprising active ingredient A (Product X); and (b) a product comprising a combination of active ingredient A and active ingredient B (‘Product Y’); and where: (c) an authorisation to place Product X on the market as a medicinal product has been granted; (d) an SPC has been granted in respect of Product X; and (e) a separate authorisation to place Product Y on the market as a medicinal product has subsequently been granted, does … Regulation [No 469/2009], in particular Articles 3(c) and (d) and/or 13(1), preclude the proprietor of the patent being issued with an SPC in respect of Product Y? Alternatively, if an SPC can be granted in respect of Product Y, should its duration be assessed by reference to the grant of the authorisation for Product X or the authorisation for Product Y?”
“38. It follows that, in order for a basic patent to protect ‘as such’ an active ingredient within the meaning of Articles 1(c) and 3(a) of Regulation No 469/2009, that active ingredient must constitute the subject-matter of the invention covered by that patent. 39. In the light of the foregoing considerations, the answer to Questions 2 and 3 is that Article 3(a) and (c) of Regulation No 469/2009 must be interpreted as meaning that, where a basic patent includes a claim to a product comprising an active ingredient which constitutes the sole subject-matter of the invention, for which the holder of that patent has already obtained an SPC, as well as a subsequent claim to a product comprising a combination of that active ingredient and another substance, that provision precludes the holder from obtaining a second SPC for that combination.”
“In 1992, researchers and clinicians were desperate to find improved treatments for HIV which was essentially still a death sentence at that time. Those working in the field were trying everything in an effort to find something that worked.”
“Applicants demonstrate that the compounds of this invention are inhibitors of HIV reverse transcriptase. The particular advantage of the present compounds are their demonstrated inhibition of resistant HIV reverse transcriptase.”
“Compounds of formula I, as herein defined, are disclosed. These compounds are useful in the inhibition of HIV reverse transcriptase (and its resistant varieties), the prevention of infection by HIV, the treatment of infection by HIV and in the treatment of AIDS and/or ARC, either as compounds, pharmaceutically acceptable salts (when appropriate), pharmaceutical composition ingredients, whether or not in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. Methods of treating AIDS, methods of preventing infection by HIV, and methods of treating infection by HIV using compounds of formula II are also disclosed.”
“For combination therapy with nucleoside analogs, a preferred dosage range is 0.1 to 20 mg/kg body weight for the compounds of this invention administered orally in divided doses, and 50 mg to 5 g/kg body weight for nucleoside analogs administered orally in divided doses.”
“The present invention is also directed to combinations of the HIV reverse transcriptase inhibitor compounds with one or more agents useful in the treatment of AIDS. For example, the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, immunomodulators, anti-infectives, or vaccines, such as those in the following Table”
“Antivirals”; “Immuno-modulators”; “Anti-infectives”; and “Other”
“A combination of a compound of Formula I as defined in claim 5 or Formula II as defined in claim 1 or 2 or a pharmaceutically acceptable salt thereof with a nucleoside analog having biological activity against HIV reverse transcriptase.” transcriptase.”
“A combination of AIDS antiviral compounds which is L734,726 [i.e. efavirenz] and L-735,524 and, optionally, one or more of the HIV inhibitors selected from the group consisting of L-697,661, AZT, ddI or ddC.”
“A combination of AIDS antiviral compounds which is L734,726 [i.e. efavirenz] and one or more of the HIV inhibitors selected from the group consisting of L-697,661, AZT, ddI or ddC.”
“A combination of the compound of claim 12 or a pharmaceutically acceptable salt thereof with a nucleoside analog having biological activity against HIV reverse transcriptase.” transcriptase.”
“The treatment of acquired immunodeficiency syndrome (AIDS) is still virtually in its infancy. 3’-azido-3’— deoxythymidine (zidovudine, AZT), the current standard therapy, was first given to a patient with AIDS only 5 years ago. Now, new drugs of several different classes are being subjected to clinical trials singly and in various combinations with zidovudine. As the history of antibiotics and antineoplastic agents has demonstrated, combination therapy with several agents often is the most effective therapy. Combination therapy may actually result in equal or superior efficacy with reduced toxicity and a reduced requirement for each agent.”
“Despite the progress made in the development of single-agent therapy for HIV-1 infection, monotherapy with either AZT, ddI or interferon-α has been associated with drug toxicity or failure [17, 26-30]. In addition, AZT-resistant varieties of HIV-1 have been isolated from patients receiving AZT as extended singleagent therapy [31-37], although the clinical implications of these findings remain uncertain. It is likely that combined therapy will be required for effective long-term treatment of HIV-1 infection, as in the approach to certain other infectious diseases (e.g. tuberculosis) and cancers [38-42]. Anti-HIV-1 combination strategies that demonstrate favourable drug interactions (e.g. synergy) may allow the use of individual agents below their toxic concentrations, provide more complete viral suppression, and limit the emergence of drug-resistant HIV-1 mutants.”
“Our data warrant expeditious investigation of combination regimens to increase efficacy and to reduce the complications that may be associated with the emergence of drug resistance. The ideal agents for use in combination regimens would be synergistic and have nonoverlapping toxicity profiles. Based on our data, initial testing of these combinations should include drug doses that provide the best therapeutic end individually. The prospect of creating antiretroviral compounds with different mechanisms of action now provides the promise of more effective long-term regimens to treat patients with HIV infection.”
“Despite the ever increasing number of agents that have been described with activity against HIV-1, monotherapy of HIV-1 infection has met with only limited success. Recent reports describing HIV-1 isolates with reduced susceptibility to single agents following prolonged therapy of HIV-1 infection in vivo [1,2] and in vitro [3] have further raised concerns over the use of monotherapy for this infection. More recently, therefore, greater emphasis has been placed on the development and investigation of combination regimens for the treatment of HIV-1 infection. Combination chemotherapy is a therapeutic strategy that has been used successfully in the treatment of other diseases including bacterial sepsis, fungal and mycobacterial infections, and malignancies. In the treatment of HIV-1 infections, combination chemotherapy offers several potential advantages over monotherapy. … … Several studies, ranging from in vitro testing to clinical trials, have now been completed or are currently underway evaluating various multi-drug regimens for the treatment of HIV-1 infections.”
“Because of its potent activity alone and the fact that Ro 318959 acts at a site different from the reverse transcriptase inhibitors, combinations of this agent with ddC and AZT were tested in vitro against both AZT-sensitive and AZT-resistant isolates [43].”
“As the number of agents with activity against HIV-1 continues to grow, so has the number of combination regimens tested in vitro against HIV-1. However, insufficient data regarding the analysis of these drugs interactions have been provided in some of these studies for us to assess synergistic, additive or antagonistic effects in vitro (Table 4). Recently, interest has focused on a series of compounds known as dipyridodiazepinones [51,52] and TIBO compounds [53] which are potent inhibitors of HIV-1 RT but not HIV-2 RT. Activity of these compounds appears to be mediated through non-competitive binding at a site separate from the template or nucleoside binding sites on the RT molecule [51, 53]. AZTsusceptible and AZT-resistant isolates of HIV-1 appear to be equally susceptible to these agents. The combination of BI-RG587 [now known as nevirapine], a dipyridodiazepinone, and AZT were shown to be synergistic in vitro against a laboratory strain of HIV-1 [54]. These encouraging results have led to the early institution of combination clinical trials of these compounds with AZT.”
“The chronic nature of HIV-1 infection, which necessitates the use of prolonged continuous therapy, coupled with the emergence of AZT-resistant mutants following extended monotherapy with AZT, suggests that future advances in the treatment of HIV-1 infection lies in the use of combination chemotherapy. Although in vitro efficacy against HIV-1 may not necessarily correlate with in vivo efficacy, properly and carefully controlled laboratory studies form an essential first step in the evaluation of potentially useful combination regimens. … It is difficult to predict what future regimens for HIV infection will be effective and widely utilized. However, it appears likely that such regimens will include several agents in combination, in sequence, or in sequential combinations. Future clinical trials based on promising leads from the laboratory should result in more effective combination therapy in the years ahead.”
“A] logical extension of current approaches for the therapy of HIV infections would be the use of combinations of multiple antiviral agents which have different antiretroviral mechanisms … Such combination therapy may enhance the antiretroviral activity and reduce the adverse effects of each drug. In addition, the development of drug-resistant HIV variants may also be delayed with the combined use of multiple drugs versus the use of single drugs.” ii) Douglas Richman et al, “BI-RG-587 Is Active against Zidovudine-Resistant Human Immunodeficiency Virus Type 1 and Synergistic with Zidovudine”, Antimicrobial Agents and Chemotherapy, 35(2), 305-308 (February 1991) (“Richman”), which is reference 54 in Mazzulli and Hirsch. Richman reported that the combination of AZT (a NRTI) and nevirapine (a NNRTI) is synergistic. Again, I also note that the authors stated (at 307): “Combination chemotherapy for HIV infection has been contemplated to increase efficacy and permit lower doses to reduce toxicity, as well as to reduce the likelihood of the emergence of drug resistance …”
“Current opinion therefore is that these agents are unsuitable for monotherapy and, at best, will only have a role to play in combination with nucleoside analogs. Given that there is increasing evidence 19 that such agents act synergistically to inhibit HIV replication in MT-4 cells whereas cytotoxic effects remain unchanged, this may still represent a modest addition to the limited repertoire of drugs available to combat AIDS.”
“The description of RT inhibitors that act at sites separate from nucleoside analogues may help limit the toxicities of those agents [43] and allow for therapeutic strategies using combinations of RT inhibitors.” ii) Jack Nunberg et al., “Viral Resistance to Human Immunodeficiency Virus Type 1-Specific Pyridinone Reverse Transcriptase Inhibitors”, J. Vir., 65(9), 4887-4892 (September 1991) (“Nunberg”), which reported inhibition of HIV-1 by three pyridinone NNRTIs, one of which was stated to be in initial safety and tolerability studies in humans. Nunberg concluded with the following statement (at 4891): “Combination therapies comprising the use of HIV-1-specific RT inhibitors and nucleoside analog RT inhibitors, such as AZT and dideoxyinonsine, will play an important role in minimizing the likelihood that drug-resistant strains of HIV-1 emerge. These treatment approaches may also benefit from potential synergism between the antiviral effects of these mechanistically different inhibitors of RT (11, 30).”
“… it may be expected that HIV-1 mutants may arise upon long-term exposure to these nonnucleoside RT inhibitors. The clinical ramifications of this will be the need for combination drug therapy where the appearance of virus resistant to both antiviral therapeutic agents will be minimized. The nonnucleoside inhibitors have already proved useful tools in understanding RT structure-function relationships. These compounds are currently undergoing clinical evaluation for their potential as the next generation of anti-AIDS therapeutics.”