Introduction to Adjuvant Patent Landscape

Adjuvants have been used since the early 20th Century to enhance an immune response to an antigen.  The need for adjuvants as a component of vaccines is still acute, especially as newer antigens may be weak immunogens or have limited availability.  Developing new adjuvants has great monetary value as well, as illustrated by acquisition of companies with adjuvant products.  Regulatory approval of adjuvants however has been almost non-existent; no new adjuvant has been approved in the United States since the 1930s and only recently has the European regulatory agency approved three vaccines with a new adjuvant. 

This patent landscape presents a first-pass overview of the adjuvant field and patenting trends in the field.  A set of patent families with subject matter related to adjuvant compositions and uses was obtained.  The set was analyzed with regard to what types of organizations are actively pursuing patents, who owns most of the patent families, and where are the patent applications filed.  Briefly, companies are more active than non-profit organizations, the top 25 or so patent owners collectively own about 40% of the families, and about 80% of the patent applications are filed in high income countries. 

The final section of this landscape provides information about some notable adjuvants, those that have been approved for new vaccines or commonly tested in clinical trials.  Some key patents encompassing these adjuvants are shown along with the broadest claims.  For this subset, in general broader claims were granted in Europe than in the United States.

This Patent Landscape is a dynamic work, and should not be viewed as definitive or comprehensive. 

This draft is authored by Dr Carol Nottenburg, Cougar Patent Law, in collaboration with CAMBIA. 

Funding for this Landscape has been provided through a grant from PATH Vaccine Solutions.

Background

Adjuvant - Any substance used in combination with a specific antigen that produces a more robust immune response than the antigen alone.  (Latin adjuvare - to help)

Adjuvants have been used since the early 20th Century to enhance an immune response to an antigen.  The need for adjuvants as a component of vaccines is still acute, especially as newer antigens may be weak immunogens or have limited availability.  The role and type of adjuvant must be critically tested and assessed in order to produce an effective vaccine - one that elicits a protective antibody response when the host is challenged with the antigen.   To provide protection, the antibody response must be of sufficient duration, sufficient affinity for the antigen, as well as appropriate subtype(s) of antibodies. 

The most commonly used adjuvants act by providing a long-lived cache of antigen, which counteracts the typical characteristic of rapid clearance and degradation of free antigen.  Adjuvants of this type are aluminum-based compounds, Freund's incomplete adjuvant (emulsion of oil and water), and microparticles.  Other adjuvants activate white blood cells, including macrophages and dendritic cells, which among other functions take up and present antigen to lymphocytes, and T cells that are required to help B cells produce antibodies.  Many of the adjuvants that stimulate immune cells are obtained from bacteria, such as bacterial lipopolysaccharide (Explanations about immune responses can be found in any basic textbook on Immunology or in the on-line course on Cellular and Molecular Immunolgy at MIT.)

Consideration of what adjuvant to use also must take into account the concomitant negative effects of adjuvants.  Many of the adjuvants lead to undesireable inflammatory outcomes.  Most readers are familiar with "flu-like" symptoms or swelling and tenderness at the injection site occurring after a vaccination.  Reducing the systemic and local unwanted effects while still providing maximal or optimal enhancement of an immune response is especially important and may drive much of the research and development of new, improved adjuvants.

In view of significant, on-going interest in and need for adjuvants and their relevance to vaccines, this patent landscape was undertaken.  As a first step to delineating and dissecting the landscape, we present here a high altitude view of world-wide patents and applications.

Image courtesy of CDC (Center for Disease Control, U.S.) and obtained from Public Image Library.

Types of adjuvants

Vaccine development has been advancing over the years.  New types of vaccines, such as DNA-based, recombinant subunits, recombinant viruses, and conjugates have been developed and introduced commercially.  These vaccines tend to be safer and less reactogenic than older-style vaccines made from live or killed whole organisms.  Use of new adjuvants that work with these vaccine types and that are less reactogenic has not kept pace with vaccine technology.  Part of the barrier is the stringent regulatory environment.   The hurdles in the U.S. and in Europe to gain approval are high (see, for example, Guideline on Adjuvants in Vaccines for Human Use by The European Medicines Agency).   In nearly 80 years since the first vaccine adjuvant was approved by the FDA (United States Food and Drug Administration), no other adjuvant has been approved by the FDA for use in humans.  The FDA only approves adjuvants in combination with vaccines and does not approve adjuvants alone.  Nevertheless, substantial investment in adjuvant technology continues as evidenced by patent application filings and by clinical studies. 

Adjuvants used in vaccines given to humans

Aluminium salts were the first adjuvants approved by the FDA for use in humans.  Use of alum salts began in the 1930s, before regulatory guidelines became more stringent.  More recently, approvals have been obtained in Europe for MF59 as an adjuvant component of flu vaccine for elderly patients (Fluad^(r) , Novartis Vaccines) and AS04 (combination of alum and MPL, GlaxoSmithKline) as the adjuvant for a viral vaccines (hepatitis B, HPV).

Categories of adjuvants in development, testing, or use

• Mineral salts - e.g., alumuninium hydroxide ("alum"), aluminium phosphate, calcium phosphate;

• Oil emulsions - e.g., MF59, a detergent-stabilised oil-in-water emulsion;
• Particulate adjuvants - e.g., virosomes, ISCOMS (structured complex of saponins and lipids);
• Microbial derivatives - e.g., MPL^(TM) (monophosphoryl lipid A), CpG motifs, modified toxins;
• Plant derivatives - e.g., saponins (QS-21);
• Endogenous immunostimulatory adjuvants - e.g., cytokines.

References

1. Glenn and O'Hagan (2007) Adjuvants: progress, regress and pandemic preparedness.  Expert Rev. Vaccines 6(5) 651-652.
2. Petrovsky et al. (2007) New-age vaccine adjuvants:  Friend or foe?  BioPharm International.
3. Vogel et al.  A compendium of vaccine adjuvants and excipients (2nd Edition)

Patent results

A set of about 653 patent families related to adjuvants were found by keyword searching.  Analysis of this set proceeded without additional screening of the claims.  Thus, this set contains not only key patents on adjuvants but also patents that may be more peripherally related to adjuvants.  For the purposes of this initial patent landscape, and assessment of trends, this set of patent families is advantageous, because additional screening could introduce bias to the set.  The set has a variety of claim types, which are discussed on the next page.

Some of the major findings include:

• the vast majority of patent owners (assignees) are corporations;
• assignees with 5 or more patent families own about 40% of all patent families in the set, with GlaxoKlineSmith having the largest share;
• all except two of the top assignees have corporate headquarters in high income countries, the two exceptions are in China;
• on average, patent families belonging to corporations are about twice as large as patent families belonging to non-profit organizations;
• the patent applications are overwhelmingly filed in high income countries (82% of patent applications) and less than 1% are filed in low income countries. 

Methodology of Patent Search

Patent data

In this report, the patent landscape of vaccine adjuvants is presented.  In particular, we focus on patents and patent applications with claims directed to adjuvants.  For a number of reasons, patent landscapes are by their nature imperfect pictures.  The major source of the difficulty is the data itself.  While it isn't possible to search patent documents in every country that has a patent system, coverage can be fairly extensive in some databases.  For the main database used, a table showing patent coverage can be viewed here.  As noted in the table, most of the country data can only be searched in a limited number of fields.  Except for a few noted countries (e.g., United States, European Patent Office) for which the entire document is searchable, the rest are searchable only in the titles, abstracts, and bibliometric fields (e.g., inventors).  In addition, the searches are conducted in English and depend on the availability of accurate translation for documents published in a language other then English. 

Other limitations on the data include incomplete historical data.  Most of the data depend upon patent offices to provide information.  While the largest patent offices, such as the United States Patent and Trademark Office, European Patent Office (EPO) and Japanese Patent Office, are diligent in electronically publishing patent data and reporting bibliographic and legal status data to WIPO (World Intellectual Property Office) and EPO, the primary compilers and distributers of patent data, patent offices in other countries range in their diligence.  The table of coverage indicates some considerable gaps of data, especially for developing countries.  For example, patent document data for Indonesia only cover 1992-1997 and for India 1975-2004. 

Search strategy

For this landscape, the primary search strategy entailed keywords.  Because vaccine terminology is well established, keyword searching was deemed to be the most appropriate approach.  The database was initially searched using the keywords "adjuvant" in the title or abstract and "vaccine" in title, abstract, or full-text.   This search was performed on 14 May 2008 and yielded 1536 patent families.  These patent families were reviewed by reading title and abstract and, in some cases, claims for patent documents directed to adjuvants. 

An additional keyword search using "immunoenhancement or immunostimulant" in title or abstract resulted in an addition 463 patent families.  Most of these however, were not directed to vaccine adjuvants but rather to therapies for cancer, for viral infections or for other diseases.  Those relevant to vaccine adjuvants were added to the previous subset of patent documents.

A total of 653 patent families were obtained of which about 50 were expired.   For the purposes of this initial landscape all 653 are considered.

Image from PCT Newsletter, June 2008

Subject matter of patent families

The collection of patent documents directed to vaccine adjuvants claim adjuvants in a variety of formats.  To say that claims come in two flavors - product claims and method claims - belies the breadth of actual claims.  Product claims to adjuvant compositions, vaccines containing adjuvant compositions, adjuvants in combination with specific antigens can range from relatively broad scope to narrow scope.  Similarly, method claims, such as to methods of producing adjuvants or to methods of stimulating an immune response, display a range of scope.  In this section, a few examples from granted patents and patent applications will serve to illustrate this point. 

Product claims that recite adjuvant compositions

The following three examples begin with a claim to monophophoryl lipid A (MLA) in a formulation.  This claim is quite broad given the long history, and advanced state, of adjuvant technology.  In fact, the importance of this patent claim, and claims of related patents, has been stated as a primary reason for GlaxoSmithKline's acquisition of Corixa.  The claim of Wyeth is also directed to MLA, but more specifically states the structure of MLA as well as precise range of amounts of other additives.  Moreover, it's narrowed by the requirement that the composition is lyophilized.  The final example claims saponin of a defined chemical structure.  Remember that in general, the narrower the claim is drafted, the easier it is to avoid infringement. 

EP 1194166 B (Corixa) An aqueous immunostimulatory adjuvant composition comprising an attenuated lipid A derivative, which is monophosphoryl lipid A or 3-O-deacylated monophosphoryl lipid A, one or more non-immunostimulatory surfactants, and glycerol.

EP 1096954 B (Wyeth) A lyophilized composition comprising 3-O-desacyl-4'-monophosphoryl lipid A in an amount up to 5% by weight, greater than 70% by weight of sugar and 0 to 30% by weight of an added amine based surfactant.

AU 764052 B (Kitasato Inst.)  A saponic compound when used as an adjuvant, said compound having a presenegenin skeleton substituted at position 28 with a sugar residue substituted with a trimethoxycinnamate residue, where the substituted sugar residue essentially comprises an apiose residue as its substituent when the substituted sugar residue is tetra-substituted.

Product claims that recite adjuvants in combination with antigen

This category of patents mostly have claims that recite a specific adjuvant in combination with a limited group of antigens.  This type of claim most likely comes about because of prior art (e.g., publications) that render a claim to the adjuvant alone unpatentable or because of other patentability requirements.  While many patent applications contain claims to a specified adjuvant in combination with any antigen, claims of this type are infrequent in granted patents that don't also claim the adjuvant alone. 

The first example is from a granted European patent and illustrates a claim to a specific adjuvant (QS-21 or MLA) along with glycoproteins from respiratory synctial virus.  Supposing that 3-deacylated MLA or QS-21 are patented as well by another entity, then Wyeth would need a license to use the adjuvant.  The second example is a claim from a patent application that attempted to claim an LFA-3 adjuvant in combination with any antigen. 

EP 0 705 109 B (Wyeth) A vaccine formulation comprising (a) a respiratory syncytial viral (RSV) protein selected from the group consisting of (i) RSV glycoprotein G, (ii) RSV glycoprotein F, (iii) a chimeric polypeptide comprising at least one immunogenic fragment from both RSV glycoproteins F and G, and (iv) combinations thereof, and (b) an adjuvant selected from the group consisting of QS-21, 3-deacylated monophosphoryl lipid A and combinations thereof, in a physiologically acceptable vehicle.  

WO 91/11194 A (Biogen) A vaccine comprising (1) an immunogenic component and (2) an adjuvant component, wherein the adjuvant comprises LFA-3 or a fragment thereof capable of binding to CD2.

Method claims for preparing adjuvant

Another type of claim directed to adjuvants is methods for preparing or making the adjuvant.  Overall, this type of claim would not keep someone else from using the adjuvant or from making the adjuvant by a different method.  Claims like these would be pursued mainly if it's the only type of protection available for the adjuvant, or the options to prepare the adjuvant are limited, or the method has a particular advantage like yield or efficacy, or it's another piece of protection used to build a wall around the subject matter. 

US 4877612 (F Berger) A process for preparing an immunological adjuvant that when administered to animals increases the immune response to antigens, and that is substantially free from mycolic acids, mycolic acid esters, and lipopolysaccharides, which comprises suspending Amycolata bacteria cells in aqueous saline solution; extracting the cells with an inert organic solvent in which the immunological adjuvant is soluble or dispersible; separating the organic solvent solution from the bacteria cells and the aqueous saline solution; and recovering immunological adjuvant.

Method claims for producing an immune response

This type of claim represents a way to protect use of the adjuvant.  In the second example, the claim was obtained in addition to claims reciting the vaccine composition.  Composition claims are generally deemed more valuable to the patent owner because they are easier to enforce.  Methods of "treating" are considered less advantageous because of difficulties in identifying and pursuing the infringer(s), the exception in the United States to infringement on the part of medical doctors, the prohibition on this type of claim in some countries. 

US 6017537 (Sanofi-Aventis) A method of enhancing the immune response of a host to an antigen of interest, comprising the steps of administering to the host a suboptimal amount of the antigen of interest and an immunogenicity-enhancing amount of an N-formyl methionyl peptide adjuvant, wherein the antigen of interest and the N-formyl methionyl peptide adjuvant are not co-immobilized on the surface of liposomes. 

US 6780421 B1(Sanofi-Aventis) A method of inducing an immune response in a mammal, comprising administering a vaccine composition comprising at least one antigen and an adjuvanting amount of 3-.beta.-(N-(N'-N-'-dimethylaminoethane)carbamoyl) cholesterol to a mammal.

Patent owners

In the area of adjuvant technology, the overwhelming majority of assignees - owners of inventions written up in patents - are corporations.  For the 653 patent families retrieved, all non-inventor assignees were determined and corporate mergers taken into account.  For example, Corixa Corporation, which was assignee in 7 families, was acquired in 2005 by GlaxoSmithKline; thus, for this analysis those 7 families were combined with those of GlaxoSmithKline.  The total number of assignees for the 653 patent families was about 1000.  The assignees that have 5 or more patent families as assignee are in the table below.  Together they own about 40% of all patent families found in the search.  GlaxoSmithKline has the largest share - 3% of the total number of families and 15% of the share owned by the top 28 assignees.  

If only the first-listed assignee is looked at, the same assignees appear as owner of 209 patent families, indicating that at least 46 of 255 patent families are co-owned with a different entity.  GlaxoSmithKline is still the assignee of the highest number of patent families however. 

Assignees - where did they file?

For the approximately 653 patent families, a breakdown of countries filed in versus the first-listed assignee was obtained.  Some trends emerged.  First, on average, companies filed in more countries than did non-profit organizations or individual inventors.  Second, the patent offices most often filed in are in Australia, Canada, Europe, Japan, United States and WIPO, regardless of the type of organization.  Third, the top assignees filed over 80% of their patent applications in high income countries and less than 1% in low income countries.  Therefore, despite the opportunity to file in low income countries, organizations do not do so. 

Companies, non-profits, and individual inventors. 

• Company assignees filed in an average of 14.7 countries, whereas non-profit organizations filed in an average of only 7.7 countries.  Individual inventors - some of whom may have already or may yet assign to an organization - filed in only 3.3 countries on average.  These data are not surprising, as non-profit organizations and individual inventors will typically have less money to spend on protecting inventions. 
• Companies and non-profits filed at approximately similar frequency in the various countries with a few exceptions.  In rough approximation, companies filed more frequently than expected in Argentina, Czech Republic, Finland, Hong Kong, Hungary, Mexico, Norway, Poland, Russia, Slovenia, Taiwan, and South Africa and somewhat less frequently in Switzerland, France, as compared to non-profit organizations.  If we exclude individual European countries, the most common countries filed in include Australia, Canada, European Patent Office,  Japan, United States, and WIPO; these 6 patent offices account for approximately 50% of all the patent filings.  These countries and Europe have large markets and especially, pharmaceutical manufacturing capability.  In our experience, organizations are less likely to file patent applications in other countries with similar profiles (e.g., Brazil, China, India); some reasons include cost, slow examination process, and difficulty of patent enforcement.  In addition, until very recently, India disallowed patents on pharmaceutical products.

Top Assignees

•  Of the assignees filing 5 or more patent families, three - GlaxoSmithKline, Wyeth, and Pfizer - each filed in an average of more than 10 countries per patent family.  The vast majority of the patent applications - 82.6% - were filed in high income countries.  Only 16.6% were filed in middle income countries and less than 1% were filed in low income countries.  The two Chinese organizations only filed in China, and the Japanese organization filed mainly in Japan.  These three organizations had the lowest average number of countries per patent family (1.0 - 1.3 average). 

Countries

For the 653 patent families, we determined in which countries patents and patent applications had been published (only published patent applications and patents are found in the patent data).  Each country is counted once per family regardless of how many patent documents are in that count.  Using this criteria - and including WIPO, the international patent office - there is a total of 4110 countries for 653 families. 

Some overcounting can occur however in the case of countries that are parties to the European Patent Convention.  This results from the European Patent Office being counted as a country, when it is a regional patent office that examines and grants patents which must then be registered in individual European countries.   Thus, if a patent application is granted by the EPO and registered in Great Britain and France, it appears that the patent occurs in three countries, when it actually is only in two countries.  If EPO is not counted at all, an undercount will result because it excludes patent applications that are pending at the EPO and not yet registered in any country.  Alternatively, all countries (34 countries as of July 2008) that are part of the EPO could be consolidated and considered as a single country - Europe.  By doing this, the count increases from 375 patent families filed at EPO to 439 filed at EPO or any EPC country, indicating that nearly all patent documents (applications and patents) in European countries are also published by the EPO.  At the same time, the total number of country publications dropped from 4110 to 3039, indicating that European patents are registered in only a few countries (2 to 3 on average). 

As can be seen in the graph below, over 60% of patent families have an application lodged and published in the EPO, WIPO, and U.S. PTO.  Other major jurisdictions are Australia, Japan and Canada.  The percentage of families with patent filings in China is intermediate between the major jurisdictions and all the others.  Within Europe, the highest numbers of patent filings are in Germany (29% of all families), Austria (22%), Spain (17%), Denmark(16%) and Great Britain (15%).  Interestingly, only 6% of all patent families have a filing in India, which has a large pharmaceutical industry.

country codes:  EP - EPO; WO - WIPO; US - United States; AU - Australia; JP - Japan; CA - Canada; CN - China; BR - Brazil; NZ - New Zealand; ZA - South Africa; KR - Korea; MX - Mexico; IL - Israel; IN - India; TW - Taiwan; HK - Hong Kong; AR - Argentina; UA - Ukraine; SU - Russian Federation; OA - OAPI (African countries); EA - Eastern Asian countries; UY - Uruguay; SG - Singapore; RO - Romania; CS - Serbia Montenegro; YU - Yugoslavia; CY - Cyprus; DZ - Algeria; GC - Arab Gulf States; MY - Malaysia; PH - Philippines.

Countries by priority year

The countries filed in according to the year of the priority document were analyzed.  For this analysis, PCT patent applications (WO) were removed, and all European patent filings were merged.  As seen in the chart, with few exceptions most of the earliest patent filings are in the United States, Europe, Australia, Japan, and Canada.  In later years, more patent applications show up in other than high-income countries. 

Country classification

Patents are often criticised for having a role in inhibiting access to medications, including vaccines, in poor countries.  Because adjuvants are a common element to vaccines, if the critics are right, then we would expect to find patent applications filed in poor countries.  And probably there would be a disproportionate number of such patent applications. 

For this aspect of analysis, we used the World Bank's classification of countries.  Their main criterion is gross national income (GNI) per capita.  Based on GNI per capita, each country is classified as high income, middle income (subdivided into upper middle and lower middle), or low income.  High income countries have a GNI per capita of over USD 11,456; upper middle income of USD 3706 - 11455; lower middle income of USD 936 - 3705 and low income of USD 935 or less.  Low income and middle income economies are sometimes called "developing economies" and roughly correspond to what some call developing countries.

The country data were first stripped of patent filings in Europe Patent Organization or WIPO.  A WIPO patent application is merely a placeholder for future patent application filings in national patent offices and as such does not reflect any single economy.  Furthermore, essentially all WIPO patent applications are originally filed in a home country, which will be counted in this analysis.  For similar reasons, EPO patent filings were not considered.  The other regional patent offices, OAPI, ARIPO, GCC, and EA, comprise multiple countries as members; patent applications in these regional offices are only filed there (rare exceptions may exist).  The GCC comprises only high income countries (Kuwait, Qatar, Oman, Saudia Arabia, Bahrain, and the Emirates), but the others comprise a mix of countries.  OAPI (Sub-Saharan Africa region) has 13 low income members, one upper middle and one lower middle income members; OAPI was grouped with other low income countries.  ARIPO (also Sub-Saharan Africa region) has 9 low income, 4 lower middle income, and 1 upper middle income country member; analysis was performed considering ARIPO as a low income economy, when analyzed as a lower middle income economy, the difference was less than 1%.  The Eurasian regional office has 1 low income, 5 lower middle income, and 2 upper middle income members; it was considered to be lower middle income.

The graph to the right illustrates that 85% of patent families have at least one patent application in a high economy country.  The remainder 15% of patent families represent either new filings for which related application filings have yet to be filed or published or applications lodged only in middle or low income countries.  Patent applications filed in a home country and then WIPO (a common scenario) will have a delay of a year or more between publication in the home country and in WIPO and publication in any other countries.  About one-quarter of patent families have an application in an upper middle or lower middle economy, while only about 2% are in low income economies.  Upper middle income countries include Brazil (14% of total families), South Africa (10% of total) and Mexico (8.5% of total).  The rest of the middle income countries (Poland, Russia, Turkey, Estonia, Croatia, Uruguay, Latvia, Romania, Serbia-Montenegro, Lithuania, and Malaysia) range from 5% down to 0.15% of total families.  The large fraction of filings in lower middle income families is mainly due to filings in China (25% of total families) and India (6%).  The other lower income countries are Ukraine and Eurasian countries (each 1.2 % of total), Indonesia, Morocco, Yugoslavia, Algeria and Phillipines, each of which is less than 0.3% of total families. 

Therefore, there doesn't appear to be substantial filing of patent applications outside of high income countries, except for China, Brazil, and South Africa (which also does not examine patent claims).  These data are a mixture of granted patents and patent applications.  The analysis does not distinguish between granted and pending patents, so it represents intentions to obtain a patent, and neither follow-through or scope of granted claims. 

Some notable adjuvants

MF59^TM is a sub-micron oil-in-water emulsion of a squalene, polyoxyethylene sorbitan monooleate (Tween^TM 80) and sorbitan trioleate.  Squalene is a natural organic compound originally obtained from shark liver oil and a biochemical precursor to steroids. The MF59 adjuvant was developed by Chiron Corp., a company acquired by Novartis.  MF59 is approved in Europe and is found in several vaccines, such as an influenza vaccine manufactured by Novartis.  It has also been licensed to other companies and is being actively tested in vaccine trials.

Other oil-in-water emulsions include Montanide (Seppic), Adjuvant 65 (in use since the 1960s), and Lipovant. 

AS02 and AS04 are proprietary adjuvants of GlaxoSmithKline (GSK).  AS02 contains MPL^TM and QS-21 in an oil-in-water emulsion.  AS02 is used in a malaria vaccine of GSK.  AS04 also is composed of MPL, but in combination with alum.  This adjuvant is used in GSK's HSV and HPV vaccine.  MPL was developed by Corixa Corp., a company purchased by GSK in order to secure MPL production for GSK vaccines.  MPL is composed of a series of 4'-monophosphoryl lipid A species that vary in the extent and position of fatty acid substitution.  It is prepared from lipopolysaccharide (LPS) of Salmonella minnesota R595 by treating LPS with mild acid and base hydrolysis followed by purification of the modified LPS. 

QS-21- A natural product of the bark of the Quillaja saponaria tree species, which is native to Chile and Argentina.  QS-21 is being tested in clinical trials with a wide variety of vaccine antigens.  Originally patented by Cambridge Biotech Corp., which went into bankruptcy and spun out its therapeutic immune system business into Aquila Biopharmaceuticals, the patents were acquired by Antigenics, Inc. in a buy-out of Aquila.  According to Antigenics, QS-21 is licensed by corporate partners, including GlaxoSmithKline, Wyeth, and Aventis Pasteur.  In return for rights to use the QS-21 adjuvant for specific diseases, the corporate partnershave agreed to pay Antigenics license fees, milestone payments, and royalties on product sales.  

ISCOMs is an acronym meaning immune stimulating complexes.  ISCOMs are honeycomb-like structures composed of typically Quillaja saponins, cholesterol, phospholipid and antigen.  Some ISCOMs are pre-formed without antigen and then mixed with antigen such that the antigen is absorbed onto or conjugated to the ISCOM. ISCOMs were initially developed in the mid-1980s by Iscotec, a company in Sweden. 

Unmethylated CpG dinucleotides are the reason that bacterial DNA, but not vertebrate DNA, is immunostimulatory.  Vertebrate DNA has relatively low amounts of unmethylated CpG compared to bacterial DNA.  The adjuvant effect of CpG is enhanced when conjugated to protein antigens.  CPG7909, an adjuvant developed by Coley Pharmaceuticals has been tested in a few vaccines, an alum-adjuvanted Hepatitis B vaccine and a CpG adjuvanted melanoma vaccine.

ADVAX, an adjuvant developed at Vaxine Pty Ltd. in Australia, is based on inulin, a natural plant-derived polysaccharide consisting of a chain of fructose molecules ending in a single glucose.  Specific isoforms, gamma- and delta-inulin, are prepare and formulated into compositions suitable as adjuvants.  For example, one formuation of gamma inulin is a pure suspension of sub-micron particles.  A synergistic effect is obtained by combining gamma-inulin with an antigen-binding material, such as inulin.  This adjuvant is called Algammulin.  Vaxine has several patent families directed to both the gamma and delta forms of inulin and is using them in vaccine trials. 

MF59 adjuvant patents

MF59 is the subject of a large patent family titled "Adjuvant formulation comprising a submicron oil droplet emulsion".  Patents have been granted in Canada, European countries of Austria, Germany, Denmark, Spain, Greece, Hungary, Ireland, Portugal - Hong Kong, Japan and the United States.  An application is also pending in the U.S.  Between the European patents and United States patents, broader claims have issued in Europe, although claims broader than already issued in the U.S. are being pursued. 

The lead claim in EP 0 399 843 B recites an adjuvant composition comprising:

• a metabolizable oil, and
• an emulsifying agent

in which the oil and emulsifying agent are in the form of an oil-in-water emulsion;

the oil droplets in the emulsion are less than 1 micrometer in diameter;and

the composition does not contain a block copolymer.

The lead claim (Claim 1) broadly encompasses oil-in-water emulsions as long as the oil is metabolizable, the oil droplets are sub-micron in size, and a block copolymer is not in the emulsion.¹  As such, this claim covers many compositions, of which MF59 is but one.  The particular formula of MF59 (squalene, polyoxyethylene sorbitan monooleate and sorbitan trioleate) isn't claimed until claim 8 (The composition of the lead claim wherein the emulsifying agent comprises a polyoxyethylene sorbitan, mono-, di-, or triester or a sorbitan mono-, di- or triester.).  The intervening claims recite particulars about the oil - an animal oil, an unsaturated hydrocaron, a terpenoid, a vegetable oil, the oil is 0.5 to 20% by volume; and about the emulsifying agent - comprises a non-ionic detergent. 

The two U.S. patents have much narrower claims.  US 6,299,884 B claims methods of stimulating an immune response by administering an antigen and adjuvant consisting essentially of:

(i) 0.5% to 20% v/v of a metabolizable oil, and

(ii) 0.01% to 2.5% w/w of an emulsifying agent,

in which substantially all the oil droplets of the oil-in-water emulsion are about 100 nm to less then 500 nm diameter,

and the composition does not contain either any polyoxypropylene-polyoxyethylene block copolymer or muramyl peptide. 

US 6,451,325 claims an adjuvant composition consisting essentially of:

(i) 0.5% to 15% v/v of a metabolizable oil,

(ii) 0.01% to 2.5% w/w of an emulsifying agent, and

(iii) an antigen

in which substantially all the oil droplets of the oil-in-water emulsion are about 100 nm to less then 500 nm diameter,

the antigen is not present in the internal phase of the adjuvant composition, and

the composition does not contain any polyoxypropylene-polyoxyethylene block copolymer.

"Consisting essentially of" carries a special meaning in U.S. patent claims.  The transitional phrase "consisting essentially of" limits the scope of a claim to the specified materials or steps "and those that do not materially affect the basic and novel characteristic(s)" of the claimed invention.  In other words, some additional ingredients will still render a composition infringing, but not if the ingredients considerably alter the essential quality of the claimed invention.  There isn't a bright line rule for someone to know which additional ingredients will allow the compostion to evade the claims.  It needs to be evaluated on a case-by-case basis and a showing of evidence of alterations will likely be required to sway a court to a finding of non-infringement. 

Claims being pursued in US 10/246,195 currently (as of March 2008) recite a composition comprising:

(i) an adjuvant comprising

4-5% v/v squalene and

an emulsifying agent consisting essentially of polyoxyethylenesorbitan monooleate and sorbitan trioleate,
in which the total amount of the sorbitan ingredients is about 1% w/w;
substantially all of the oil droplets of the oil-in-water emulsions are less then 1 micron diameter; and
there isn't any polyoxyproplylene-polyoxyethylene block copolymer;

(ii) an antigenic substance

in which the antigenic substance is from a virus, a bacterium or a parasite; and
the antigenic substance is not present in the internal phase of the adjuvant composition. 

Even though the United States Patent Office is often accused of issuing too broad claims, in this case, it is the European Patent Office that has issued very broad claims.  All the U.S. claims - patented or pending - are a fair bit narrower in scope.

1 - In a series of patents, all of which are now expired, Syntex had patented an adjuvant composition that contained an immunopotentiating amount of an immunostimulating glycopeptide, a polyoxypropylene-polyoxyethylene block polymer, a glycol ether-based surfactant, and, optionally, a metabolizable non-toxic oil.  These patents are likely why a block co-polymer is excluded from the MF59 claims.  Note that some of Syntex patents directed to similar subject matter are still in force.

MPL and AS02/AS04 adjuvant patents

MPL patent

MPL^TM, patented by Corixa Corp., is protected by patents in quite a few countries.  Patents are found in Australia, China, European countries of Austria, Germany, Denmark, Hungary, Norway, Poland, Portugal, Spain,  Turkey; Hong Kong, New Zealand and the United States.  Applications were also filed in Brazil, Canada, and Israel. 

The patents are drawn to an attenuated form of the lipid A component of bacterial lipopolysaccharide (LPS).  LPS, and lipid A, are potent immunostimulators but have deleterious side effects, such as pyrogenicity (fever).  The modifications described in Corixa's patents abate the side effects but do not disable the immunostimulatory effects of lipid A. 

AS04 patents

Patents have issued in Australia, Europe (Austria, Germany, Denmark, Spain, Hungary, Luxembourg, Norway, Poland, Turkey) New Zealand, Taiwan, and the United States.  Patent applications were filed in Brazil, Canada, Israel, India, Japan, and there is a divisional patent application pending in Europe. 

AS02 patents

A patent family directed to vaccine compositions comprising 3D-MLA and QS21 is owned by GlaxoSmithKline.  In this very large family, patents have been granted in Australia, Canada, China, Czech Republic, Hong Kong, Israel, Japan, New Zealand, Russia, Singapore, the United States and Europe (Austria, Germany, Kenmark, Spain, Finland, Great Briatain, Greece, Hungary, Norway, Poland, Portugal, Slovenia, Slovakia).  Some of the patents claim specific vaccines, such as a vaccine comprising an HIV antigen, QS21 and 3D-MPL.  The claims in the table below are not constrained to a particular antigen. 

QS-21 adjuvant

Antigenics' patent family that claims QS-21 is large.  Patents are held in Australia, Canada, European countries - Austria, Germany, Denmark, Spain, Norway - Japan, New Zealand and the United States.  The U.S. patents expire in 2008 and in 2013, and the European patents expire in 2008 and 2012. 

In addition, other patent families, owned by GlaxoSmithKline, claim QS21 in combination with a sterol, such that the composition is in the form of an ISCOM (e.g., US 6846489) or claim QS21 as part of a oil-in-water emulsion in which the ratio of oil:saponin is 48:1 (e.g., EP 1 279 401 B). 

Unmethylated CpG dinucleotides

The key patent families are co-owned by Coley Pharmaceuticals, University of Iowa, and the U.S. Government.  The earliest filing of patent applications has resulted in a huge extended family of patents and patent applications in Australia, Canada, China, Europe (Austria, Germany, Denmark, Portugal) Japan, Korea, New Zealand and the United States.  The broadest European and United States patents are presented in the table below.  Other European patents and United States patents are directed to CpG oligos for treatment of asthma, or ex vivo treatment of lymphocytes, and to CpG oligos having a defined sequence. 

A second, smaller patent family owned by Coley Pharmaceutical, Ottawa Health Research Institute and University of Iowa claims a composition which is a synergistic combination of adjuvants, comprising at least one non-nucleic acid adjuvant and at least one unmethylated CpG oligonucleotide (e.g., US 6,406,705 B1).  Antigenics has a patent family directed specifically to the synergistic combination of a saponin and unmethylated CpG oligo (e.g., EP 1 104 306 B). 

The information contained in this page was believed to be correct at the time it was collated. New patents and patent applications, altered status of patents, and case law may have resulted in changes in the landscape. CAMBIA makes no warranty that it is correct or up to date at this time and accepts no liability for any use that might be made of it. Corrections or updates to the information are welcome, please send an email to info@bios.net.