patent search on biologics as potential biosimilar candidates
TRANSCRIPT
World Patent Information 33 (2011) 67–71
Contents lists available at ScienceDirect
World Patent Information
journal homepage: www.elsevier .com/locate /worpat in
Patent search on biologics as potential biosimilar candidates q
Sunny WangGlobal Patent Operation and Support, Sanofi-aventis, 1041 Route 202-206, Bridgewater, NJ 08807, USA
a r t i c l e i n f o
Keywords:Biologics:biosimilars:follow-on biologicsBiopharmaceuticalsFTO searchKeyword searchingSequence searchingSemantic searching:Enbrel:patent
0172-2190/$ - see front matter � 2010 Published bydoi:10.1016/j.wpi.2010.05.001
q This article has been developed from a presenInternational Patent Information Conference, IPI-ConfMestre, Italy.
E-mail address: [email protected]
a b s t r a c t
The biological pharmaceutical market is one of the fastest growing sectors in the health care business.Sales of biologic drugs reached $120 billion in 2008 [1] and the worldwide market of biologics continuesto grow (IMS Health). As patents on first generation of biologic drugs, including epoetin, insulin granu-locyte colony-stimulating factor (G-CSF) and interferon alpha, will soon expire, if they have not already,and patents on some of the second generation of biological drugs, such as antibody drugs, are going to beexpire in the next few years, there exists a great opportunity in developing biosimilars, especially forlarge pharmaceutical companies which face great challenges in developing new blockbuster drugs. Inthe past few years, the United States, Canada, and Japan have debated or passed legislation on biosimilarswith active involvement from top pharmaceutical and generic drug companies. The successful leader inthis field will be the one that has the foresight and resources to position themselves well to gain in thefuture. So what are biosimilars? What are the technological differences between biosimilars and smallmolecule generic drugs? Finally, what are the considerations for biosimilars in terms of patent searching?An example on a biosimilar study is given here.
� 2010 Published by Elsevier Ltd.
1. Introduction So what are biosimilars? And why is there a lot of recent atten-
Biosimilars have become a buzzword in recent years. When theterms of ‘‘biosimilar or follow-on bio” (truncated form of biologic)are searched for on ‘‘Google news”, a Timeline bar graph shows thesteep increase in the number of News Articles published form 1980to 2009 (adjustable dates). Clicking on the blue bars brings up thecollection of articles (Fig. 1).
The European Medicines Agency (EMEA) has moved ahead ofthe rest of the world in this area. It established a biosimilar regu-latory pathway in 2004 and published the ‘‘Guideline on SimilarBiological Medicinal Products” in 2005 [2]. Since then it has ap-proved a number of biosimilar products in a declared, balancedprocess. The United States has been very cautious on moving inthe same direction and the legislative pathway for biosimilar ap-proval is still being debated [3]. Health Canada is working on thesame issue by drafting the guidelines, called Subsequent EntryBiologics (SEBs) [4], while Japan’s Ministry of Health, Labor andWelfare (MHLW) recently adopted biosimilar regulations [5] thatare similar to the European Union approval system. In June 2009,Japan announced its first approval of a biosimilar human growthhormone (HGH) product [6].
Elsevier Ltd.
tation by the author at theEx, in March 2009, in Venice
tion on them?
1.1. Definition of biosimilars
First, there are biologics (biologic pharmaceuticals or biophar-maceuticals). Biologics or biopharmaceuticals are a subset of drugsthat are generated from biological sources and include gene thera-pies, vaccines, antibodies, and other therapeutic products derivedthrough biotechnology [7]. They were ‘‘officially” introduced tothe market as ‘‘biologic drug” in the early 1980s. Only in 1982did recombinant human insulin become the first biotech therapyto earn FDA approval and arrive on the market [8], even thoughthe first two biologics, insulin and HGH, had been on the marketin the United States for a long time, simply without biologic titles.
Biosimilars, also called follow-on biologics (FOB) or SubsequentEntry Biologics (SEBs), refer to ‘‘generic” version of biologics or bio-pharmaceutical products that are produced and sold on the marketafter the patents on the innovator’s biologics are expired. However,the nomenclature of biosimilars is not universal. For example:
Wikipedia definition [9]:Biosimilars or follow-on biologics are terms used to describeofficially approved new versions of innovator biopharmaceuticalproducts, following patent expiry.
EMEA definition [2]:A new biological medicinal product claimed to be ‘‘similar” toa reference medicinal product, which has been granted a
Fig. 1. Snapshot of the web site Google news for a search on ‘‘biosimilars or follow-on bio” from 1980 to 2009.
68 S. Wang / World Patent Information 33 (2011) 67–71
marketing authorization in the Community on the basis of acomplete dossier. . . e.g.: medicinal products containing biotech-nology derived proteins as active substance, immunologicals suchas vaccines, blood-derived products, monoclonal antibodies, etc.
US Congress definition [3]:The biological product:
(I) is biosimilar to the reference product and any biologicalproduct licensed. . .
(II) can be expected to produce the same clinical result asthe reference product in any given patient for each con-dition of use prescribed, recommended, or suggested inthe labeling of the reference product. . .
Canada Health definition [4]:A SEB is defined by Health Canada as ‘‘a biologic product thatwould enter the market subsequent to, and similar to, an inno-vator product authorized for sale in Canada.”
In summary, a biosimilar is a biological product which is similarto the referenced product ‘‘approved before” and ‘‘on market”, andis expected to have substantially similar clinical results (in terms ofsafety profile and efficacy) of the referenced product. For morereading about biosimilars, such as related to bioequivalence, clini-cal safety and efficacy, regulatory, policy and legal issues, pleaserefer to listed reviews [10–15].
1.2. Types of biologics or biosimilars
People normally think of biologics as proteins or antibodies, butbiologics can be gene therapies, vaccines and other biological ther-apeutic products too.
The therapeutic proteins, such as epoetin, insulin, G-CSF andinterferon alpha, are well known as the first generation biologics.Monoclonal antibodies are the current success stories of modernbiotechnology. Availability of human and humanized monoclonalantibodies or chimeric protein-antibody has increased the successrate in clinical trials of cancer and immuno-inflammatory diseaseslike rheumatoid arthritis. The global sales of monoclonal antibodieswere $27 billion in 2007 and $33 billion in 2008 (IMS Health data).
1.3. Biosimilars on the market
In the light of the expiration of a number of patents on first gen-eration biologics, EMEA has approved about 13 biosimilars (relatedto three proteins, six drug products) so far [16]. The first two bio-similars are HGH products, Omnitrope and Valtropin. Five biosim-
ilar epoetins products—Binocrit, Epoetin alfa Hexal, Abseamed,Retacrit and Silapo, have been approved, and six, G-CSF productshave received approval from EMEA. They are TevaGrastim, GRA-STIM, Filgrastim-Mepha, Grasalva, Ratiograstim, and Biograstim.
1.4. Differences between biosimilars and generic drugs
The differences are clear. Biosimilars are macro biologic mole-cules; have complicated primary, secondary and tertiary struc-tures; and are expressed in living cells, and generic drugs are thelow molecular weight compounds, normally synthesized by chem-ical reactions.
The living cells that produce biologics can be sensitive to veryminor changes in the process of making the biologic. In contrary,a manufacturing process for small-molecule drugs can be alteredas long as the finished product is analyzed by laboratory tests toestablish that it is the same product.
For small molecules, the bioequivalence of the generic drug isdemonstrated through relatively simple analyses such as blood leveltesting, without the need for further human clinical trials. However,current analytical methods cannot characterize these complex bio-logical molecules sufficiently to confirm structural and functionalequivalence with reference molecules; as such, interchangeabilityof biosimilars to the reference product is questionable [17].
2. Search on biologics as potential biosimilar candidates
Searching biologics can be difficult and time-consuming due tothe complex of their biological structures and properties of macromolecules. The key considerations for such searching are:
2.1. The patent owner of a biologic drug tends to file patentapplications aggressively to protect the drug. The patentfamily could be large containing hundreds of patent familymembers.For example, a patent family (US5656272) covering Remi-cade (Infliximab) assigned to the New York University Med-ical Center and Centocor, Inc. (Johnson & Johnson subsidiary)contains 170 publications, 115 applications, and 79 priori-ties (INPADOC family). For US filings alone, there are 37issued patents and 59 published applications. For patentsearchers and patent analysts, the challenge is to figureout which patents cover the product and which do not.
2.2. Not only are patents on composition matters important, butpatents on production methods or process of making arecritical too.
S. Wang / World Patent Information 33 (2011) 67–71 69
For example, US Patent 4703008 (claimed its DNA andencoded amino acid) for Amgen’s first biologic drug, Epogen,expired on October 27, 2004, but Epogen is still covered byits process patents (US5955422; US5547933; US5441868;US5618698 and US5756349) which will not expire until2013 (IMS Patent Focus).
2.3. A patent owner continues to file new patents related to thedrug product and technologies along the drug developingprocess.For example, Genentech filed US4816567 to claim recombi-nant immunoglobin preparations of Trastuzumab (Hercep-tin). Later, the company continued to file several patentfamilies, such as US6267958, to cover a stable lyophilizedformulation of drug, US6627196 to claim dosages for treat-ment, and US7038017 to claim antibody purification, andmore. Even after first patent expires, a new application couldhave been just filed.
2.4. Multiple companies work on similar biologic molecule andfiled patents. As a result, multiple licenses from other patentowners likely are needed for developing and marketing abiologic drug.For example, the biologic drug Enbrel/Etanercept, a fusionprotein acting as a tumor necrosis factor (TNF) receptorinhibitor, was developed by Immunex (later acquired byAmgen). However, Genentech, BASF, Hoechst (now sanofi-aventis), Yeda, Roche and other companies possessed pat-ents related to earlier discoveries of mammalian TNF recep-tor. Those patents should be considered in an Enbrel/Etanercept FTO search.
3. Other considerations for searching
3.1. Drug databases
Since the biologics are approved and on market, it is reasonableto check the databases containing drug and patent coverage, suchas IMS Knowledge Link or Thomson Reuter Partner IDdb.
Canada Register covers a good number of biologics and offers afree resource to start with.
3.2. Sequence searching
For the majority of biosimilars or potential developing targets,the key approach is sequence search (refer to both nucleotide se-quence and protein sequence searches). Just like searching onchemical molecules, chemical structure is the universal languageof chemistry and structure searching is an essential skill for achemical searcher or analyst; the sequence is the universal labelfor a particular biologic.
A sequence searching program is expected to report not onlyexact matches, but fragments of identities and, most importantly,similar sequences, so that the mutants with a few changes in se-quence can be detected. The main considerations for sequencesearching are:
Not just 100% matches are relevant:Especially true for Enbrel case, the sequence of the first patentfamily covering the product (US5395760; US5605690;US5945397; RE36755) only matches the first 235 amino acidsof the complete 467 amino acid sequence of Enbrel (CAS#185243–69-0).Not all 100% matches are relevant:In developing a biosimilar, the patenting on composition, pro-cess of making, formulation or method of use are all relevant,but patenting gene expression might not be—even through thegene in ‘‘gene expression” is a 100% match to the target gene.
3.3. Keyword searching
Keyword searching can find exact matches from text (either ti-tle, abstract, bibliographic information, specification or claims).The main considerations for keyword searching are:
Synonyms for a biologic including brand name and generic nameFor example, tumor necrosis factor alpha-induced protein 1(TNFAIP1) has the following synonyms: B12, B61, BTB/POZdomain-containing protein TNFAIP1, EDP1, MGC2317, proteinB12 [18], etc. However, not all synonym names need to besearched for biosimilar searching. It requires a good under-standing of bioscience and subject to decide what synonymshould be included and what should not. A discussion with sci-entists in the field and patent attorney in charge of the projectcan be helpful.
Spelling variations and truncated formsThey are common searching techniques.
Abbreviations and acronymsFor example, TNF-R2 is referring to tumor necrosis factor recep-tor 2, both terms should be searched.
3.4. Semantic searching
According to Wikipedia, ‘‘semantic search is a process used toimprove online searching by using data from semantic networksto disambiguate queries and web text in order to generate morerelevant results”. Semantic search is catching up in the searchingfield, but it has its limitations. The key consideration when dealingwith semantic searching is the following:
It is broader than a keyword search but false hits are much higherFor example, Enbrel semantic search on LexisNexis TotalPatentgenerates over 2000 hits. It not only includes Etanercept orhuman TNF receptor, etc. in the search but also includes othersimilar TNF drugs, such as Remicade/Infliximab, Lenercept,Humira, etc. in the search terms, which are not the fusion protein.
3.5. Post search processing
Post search processing is always an important step for search-ing. However, how to process and to what extent will depend onthe clients’ requests.
4. Search example: Enbrel
Searching strategies and techniques always depend on subjects.FTO searches on biosimilars are no exception.
4.1. Enbrel, what is it?
Enbrel, a trade name of etanercept, is an FDA-approved drug totreat rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriat-ic arthritis, and juvenile rheumatoid arthritis [19]. Enbrel is a fusionprotein produced through expression of recombinant DNA thattreats autoimmune diseases by interfering with the TNF receptor(a part of the immune system) by acting as a TNF inhibitor.
4.2. Market
According to IMS Health, the worldwide sale of Enbrel is about$5.5 billion in 2008 (12 months up to 4th quarter of 2008). Notonly is Enbrel one of the top biologic drugs, but drugs in the same
Table 1Search strategy summary for Enbrel FTO searching.
Searchapproach
Databases Notes
Keyworda
searchWpix andQuestel Orbit
Enbrel, Etanercept, TNF chimericprotein, tumor necrosis factor receptor2, TNF-R2, tumor necrosis factorreceptor type II, TNF-RII, TNFR-II, p75,p80 TNF-alpha receptor, CD120b,p75TNFR, TBPII, TNFBR, TNFR1B,TNFR2, TNF-R2, TNF-R75, TNFR80
STN search Caplus Registry #, Control Term (CT) andkeywords
Semantic search LexisNexisTotalPatent
Enbrel or Etanercept
Concept search Patentics US5395760 (full document search)Sequence
searchGenomeQuestand Dgene
Single chain of Enbrel (467 amino acids)and full length of SEQ ID NO 2 of RE36755
Drug search CanadaRegister,IMS KnowledgeLink, IDdb
Enbrel or Etanercept
STN, Scientific and Technical Information Network.a Note: keywords are from Genbank link: http://www.ncbi.nlm.nih.gov/nuccore/
23312365 and IHOP-net: http://www.ihop-net.org/UniPub/iHOP/gs/92775.html.
Fig. 2. Patent Term Extension for Immunex (now Amgen) reissued Patent RE36755.
70 S. Wang / World Patent Information 33 (2011) 67–71
class on the same target, TNF, such as Remicade and Humira, allshow market success in 2008.
4.3. Search on Enbrel
The search strategy and databases are listed in Table 1.There are some considerations for this search:
(1) This combined keyword/STN/semantic search can generateover 1000 hits. The keyword list (synonym names) can beedited accordingly. And searching could be limited to‘‘claims” only (full text search).
(2) The full length of Enbrel sequence consists of 934 aminoacids. It is a dimer containing two identical 467 amino acidportions listed on CA Registry (CAS #185243–69-0). How-ever, first patent listed for covering the drug is not AmgenUS7276477 (Crystals of Etanercept and methods of makingthereof), but US5395760 (Immunex/Amgen, reissued asRE36755) (DNA encoding tumor necrosis factor alpha- andbeta-receptors)—see Fig. 2 also.
(3) Only the first 1–235 amino acid sequence of SEQ ID NO 2 ofRE36755 was used for making the drug. Therefore, it onlymatches first half of Enbrel (not 100% identical).
(4) Formulation.
Do not forget formulation patent for biologics.
PATENTICS (www.patentics.com) offers a concept search, whichis very helpful for biologic formulation searching.
(5) Post process.
All search results from different databases should be combinedfor a full analysis before being reported to clients. Although the re-port should be structured to clients’ demands and focuses, the re-port for a biosimilar FTO should contain the following information:
Patents claiming composition.Patents claiming process of making, including vector and celllines.Patents claiming formulation.Patents claiming particular use (which clients are interested in).
5. Summary
There are over 60 million patents or applications recorded in avariety of databases, so far, and massive growth of patent informa-tion is occurring at a robust pace. It is no wonder that patentsearching can often be reminiscent of looking for an ever smallerneedle in an ever bigger haystack.
The challenge has been ever further amplified when dealingwith biologics patent searching. As mentioned above, many syn-onyms for biologic targets, large patent families, and complicatedtechnologies, e.g. bispecific or multivalent and multispecific anti-body, can make bio searching be ever more of a challenge.
However, successes in biosimilar searching can be attained bycombining various conventional (drug register, keyword, sequencesearch, etc.) and non-conventional methods (semantic or conceptsearch). The final report should include a set of patents which fullycovers the product and related technologies.
Acknowledgements
I gratefully acknowledge John Conway, the Vice President andGlobal Head Innovative Healthcare Patent Support of sanofi-aven-tis for his advice and support. John kindly granted me his valuabletime for discussion with me and I benefited a lot from his knowl-edge and insight on biosimilars. Also many thanks go to two ofmy team members, Piotr Masiakowski and May Xuemei Peng. Bothhave done a lot of work on biosimilars and they offer me a greathelp in many ways far beyond this project.
References
[1] Maggon K. Global pharmaceutical market review and world top ten/twentydrugs. <http://knol.google.com/k/global-pharmaceutical-market-intelligence-monograph#>; 2008.
[2] European Medicines Agency. Guideline on similar biological medicinalproducts. <http://www.emea.europa.eu/pdfs/human/biosimilar/043704en.pdf>; 2005.
[3] US 110th Congress. H.R. 5629, 2d Session. Pathway for biosimilars act. <http://http://www.govtrack.us/congress/billtext.xpd?bill=h110-5629>; 2008.
[4] Health Canada. Draft guidance for sponsors: information and submissionrequirements for subsequent entry biologics (SEBs). <http://www.hc-sc.gc.ca/dhp-mps/brgtherap/activit/consultation/seb-pbu/2008-tc-tm-eng.php>; 2008.
[5] IHS Global Insight. MHLW issues guidelines on biosimilars development andregulatory applications. <http://www.ihsglobalinsight.com/SDA/SDADetail16336.htm>; 2009.
[6] Novartis Media Release. <http://www.novartis.com/newsroom/media-releases/en/2009/1345623.shtml>; 2009.
[7] Reguly T, McMahon E. Biosimilars in Canada: new draft guidelines from healthCanada. Update 2009; Issue 4.
[8] Genentech Inc. Corporate chronology. <http://www.gene.com/gene/about/corporate/history/timeline.html>; 1982.
[9] Wikipedia. Biosimilar. <http://en.wikipedia.org/wiki/Biosimilar>.[10] Schellekens H. When biotech proteins go off-patent. Trends Biotechnol
2004;22(8):406–10.
S. Wang / World Patent Information 33 (2011) 67–71 71
[11] Crommelin D, Bermejo T, Bissig M, et al. Pharmaceutical evaluation ofbiosimilars: important differences from generic low-molecular-weightpharmaceuticals. Eur J Hosp Pharm Sci 2005;11:11–7.
[12] Mellstedt H, Niederwasser D, Ludwig H. The challenge of biosimilars. AnnOncol 2008;19:411–9.
[13] Gottlieb S. Biosimilars: policy, clinical, and regulatory considerations. Am JHealth-Syst Pharm 2008;65(Suppl. 6):S2–8.
[14] Kresse GB. Biosimilars – science, status, and strategic perspective. Eur J PharmBiopharm 2009;72:479–86.
[15] Hincal F. An introduction to safety issues in biosimilars/follow-onbiopharmaceuticals. J Med CBR Def 2009;7:1–18. <http://www.jmedcbr.org/issue0701/Hincal/Hincal_09_09.htm>.
[16] Dowlat HA. Fresh insights into the practicalities of developing biosimilarbiologics. <http://www.parexelconsulting.com/files/articles/2009_10_Focus_Dowlat_Biosimilars.pdf>; 2009.
[17] BIO (Biotechnology Industry Organization). Biosimilars. <http://bio.org/healthcare/followonbkg/>.
[18] IHOP-net. TNFAIP1. <http://www.ihop-net.org/UniPub/iHOP/gs/92768.html>.[19] Wikipedia. Etanercept. <http://en.wikipedia.org/wiki/Etanercept>.
Sunny Wang heads the Patent Search Group of GlobalPatent Operation & Support at sanofi-aventis. Her grouphas the overall responsibility in supporting patentattorneys globally for all aspects of scientific and patentinformation search. She is a US PTO registered patentagent since 2003. She has more than nine years expe-rience in biotech search and patent analysis. Prior tobeing an information specialist with Patent Bar qualifi-cation, she was a molecular biologist with over fifteenpeer-reviewed scientific papers and book chapterspublished as first author or co-author. Educated inChina with a B.S in Biochemistry, she graduated from
the University of North Carolina at Chapel Hill with a Master degree in BiologicalChemistry. She currently serves as a member of the ACS Joint Board-CouncilCommittee on Chemical Abstract Service (CCAS).