Patents and nanomedicine

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Patents and nanomedicine

1Bawa Biotechnology Consulting, LLC, 21005 Starflower Way, Ashburn, Virginia 20147, USA2Rensselaer Polytechnic Institute, Troy, NY, USATel.: + 1 703 582 1745; +1 703 723 0034;Fax: +1 571 223 1844;E-mail: [email protected]

The author is a registered patent agent licensed to practice before the US Patent and Trademark Office and Fellow of the American Academy of Nanomedicine

part of

Keywords: commercialization, drug delivery, nanomedicine, nanoparticles, National Nanotechnology Initiative, nonexclusive licensing, patent classification, patent thickets, US Patent and Trademark Office

10.2217/17435889.2.3.351 © 2

Big pharma’s business model, which relies on a few blockbusters to generate profits, is clearly broken. Patent expiration on numerous blockbusters in recent years is already altering the drug landscape. Drug companies are also facing other challenges that necessitate development and implementation of novel R&D strategies, including those that focus on nanotechnology and miniaturization. Clearly, there is enormous excitement and expectation regarding nanomedicine’s potential impact. However, securing valid and defensible patent protection will be critical. Although early forecasts for nanomedicine commercialization are encouraging, there are numerous bottlenecks as well. One of the major hurdles is an emerging thicket of patent claims, resulting primarily from patent proliferation as well as continued issuance of surprisingly broad patents by the US Patent and Trademark Office (PTO). Adding to this confusion is the fact that the US National Nanotechnology Initiative’s widely cited definition of nanotechnology is inaccurate and irrelevant from a nanomedicine perspective. It is also the cause of the inadequate patent classification system that was recently unveiled by the PTO. All of this is creating a chaotic, tangled patent landscape in various sectors of nanomedicine where the competing players are unsure of the validity and enforceability of numerous issued patents. If this trend continues, it could stifle competition and limit access to some inventions. Therefore, reforms are urgently needed at the PTO to address problems ranging from poor patent quality and questionable examination practices to inadequate search capabilities, rising attrition, poor employee morale and a skyrocketing patent application backlog. Only a robust patent system will stimulate the development of commercially viable nanomedicine products that can drastically improve a patient’s quality of life and reduce healthcare costs.

New paradigms are shrinking our world and atechnological revolution in medicine is unfold-ing. Nanomedicine [1,2], a newly emerginginterdisciplinary field and part of the high-risk,high-payoff global nanotechnology phenome-non, has yet to establish itself fully, althoughthere are a few nanomedicine products on themarket and many more potential applicationsunder consideration. Commercial nano-medicine is at a nascent stage of developmentand the full potential of nanomedicine is yearsor decades away. However, make no mistake,recent advances in nanotechnology-related drugdelivery, diagnosis and drug development arebeginning to alter the landscape of medicine.Towards this goal, significant technologicaladvances across multiple scientific areas ofnanomedicine will continue to be proposed,validated, patented and commercialized. Drugdelivery is one area that will produce significantresults here. For example, site-specific targeteddrug-delivery systems (DDSs), with theirpotential to address unmet medical needs(made possible by the availability of unique

nanomaterial delivery platforms, such as den-drimers, nanoshells, nanoparticles and nano-liposomes) and personalized medicine (a resultof advances in pharmacogenetics and pharma-cogenomics) are on the horizon. Other morefuturistic targeted drug-delivery approachesinvolve ‘nanofactories’, in which biological mol-ecules found in vivo can be converted intoactive biotherapeutics in response to a localizedmedical condition.

Early forecasts for nanomedicine commercial-ization are encouraging but there are formidablechallenges as well. These include legal, environ-mental, safety, ethical and regulatory questionsas well as emerging thickets of overlapping pat-ent claims. Patent systems in general are undergreater scrutiny and strain, with patent officesaround the world continuing to struggle withevaluating the swarm of nanomedicine-relatedpatent applications. There is great concern todayover the inherent health risks and safety of somenanomedicines. Government regulatory agenciesare grappling to formulate an appropriate set ofguidelines, a difficult task given the current level

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of uncertainty regarding such health risks. How-ever, I believe that current fears about self-repli-cating nanobots, the potential toxic effects ofnanoparticles and the resultant calls for strictregulatory oversight or a nanotech moratoriumwill eventually give way to intelligent public dia-log on the realistic impact of nanomedicine (andnanotechnology).

Given this backdrop, it is natural to questionwhether nanomedicine-related advances in thelaboratory will result in viable commercial prod-ucts that benefit society, or whether certain bot-tlenecks and unforeseen problems will preventtheir introduction to the marketplace. One thingis clear: nanomedicine is here to stay and willgenerate both evolutionary as well as revolution-ary products in the future, thereby improving allaspects of our lives.

Drug industry & nanomedicine: a need for miniaturizationThe need for drug companies to focus on tech-nologies that support miniaturization and high-throughput (which enables faster drug targetdiscovery and drug development) is real andurgent. US drug companies in today’s globaleconomy face enormous pressure to deliverhigh-quality products to the consumer whilemaintaining profitability. They must constantlyreassess how to improve the success rate of newchemical entities (NCEs) while reducing R&Dcosts as well as cycle time for producing newdrugs. This is especially true for new blockbust-ers. In fact, the cost of developing and launch-ing a new drug to the market, although widelyvariable [3,4,101], may be upwards ofUS$800 million. Typically, the drug appears onthe market some 10–15 years after discovery [5].Furthermore, for every 8000 compoundsscreened for potential drug development, onlyone makes it to clinical use [6] and only one outof five lead compounds makes it to final clinicaluse [7]. Annual R&D investment by drug com-panies has risen from US$1 billion in 1975 toUS$40 billion in 2003, while new approvalshave essentially remained flat – 20–30 drugs peryear [8]. In fact, for the past few years, NCEsaccounted for only 25% of products approved,with the majority of approvals being reformula-tions or combinations of already approvedagents [6]. While the cost of drug R&D contin-ues to rise, only 30% of drugs are able to recovertheir R&D costs. The weakened product pipe-line issue is a global problem; the decreasingnumbers of new drugs approved by the US FDA

and foreign drug agencies continues to hauntthe drug industry. For example, FDA approvalshave fallen by half since 1996, with only 20approvals in 2005.

The drug industry is currently facing otherrelated hurdles as well:

• Increased pressures to keep healthcare costsaffordable and a demand by patients andhealthcare providers for added value;

• An increase in the global generics’ share of theprescription-drug market;

• International competition from low-costcenters, like India and China (especiallywith respect to generic competition, pricingpressures, clinical trials and manufacturing);

• Forced or voluntary withdrawal of severaldrugs in recent years (as highlighted byMerck’s Vioxx and Scientific’s Taxus);

• For the first time, expiration of patents onblockbusters is altering the drug landscape(According to Merrill Lynch [9], 23 of thetop global pharmaceutical patents will expireby 2008, accounting for an annual revenueloss of more than US$46 billion. In fact,various reports project that drug revenuesworth US$70–80 billion will be lost by2011 as various drugs go off-patent);

• State and federal government’s increased vigi-lance pertaining to hyperaggressive businesspractices, especially illegal drug marketing andimproper drug pricing (∼150 cases of allegedfraud by drug companies are currently on theJustice Department’s docket [10]);

• Difficulty or inability in effectively formu-lating active agents due to the fact that30–40% of all active agents identified viacombinatorial screening programs have poorwater solubility;

• Unique drug-development models are beingsuccessfully developed to circumvent somepatented branded drugs [11];

• Difficulty in delivering promising compounds,such as peptides, proteins and other therapeuticbiologicals (generated as a result of the rapidgrowth of the global biotechnology industry);

• Pricing pressures because of high industryprofit margins;

• A gradual erosion of public confidence in thedrug industry in recent years;

• Quality and performance problems at the FDAand the US Patent & Trademark Office (PTO).

Given all these critical issues and problems, itis evident that the current business models ofdrug companies (with their mammoth size and

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excessive reliance on blockbusters) are brokenand in need of a fix. There is a critical need fordrug companies to alter research approaches andbusiness models so that they can continue to dis-cover and fill the pipeline with novel compoundsand rapidly introduce them to new markets.Clearly, numerous factors are dictating that newdrug discovery, development and deliveryapproaches be developed and implemented.

This is where nanomedicine can impact theindustry and save the day. In other words,although the aforementioned trends are creat-ing novel challenges for the drug industry, theyalso represent a great opportunity to focus onnanoenabled R&D technologies. At this stage,however, several obstacles beset nanoenabledR&D and nanomedicine commercializationefforts, including: • High production costs;

• The public’s general reluctance to embraceinnovative medical technologies without realsafety guidelines;

• Relative scarcity of venture funds;• Few near-term commercially viable products;• A general lack of knowledge regarding the

interaction between nanomaterials and livingcells (the issue of biocompatibility and toxicityof nanomaterials);

• Big pharma’s reluctance to seriously invest innanomedicine;

• Production issues, such as lack of quality con-trol, reproducibility and scalability of mostnanostructures of commercial interest;

• Confusion and delay at the PTO (withrespect to the burgeoning number of nano-medicine-related patent applications) andthe FDA (with respect to a lack of clearregulatory/safety guidelines);

• The media’s continuing focus on the negativeaspects of nanomaterials, especially nano-particulate nanomedicines, often withoutproper scientific evidence (environmental,health and safety concerns are at the forefront).

Nevertheless, governments around the worldare impressed by nanotechnology’s potential andare staking their claims by doling out billions ofDollars, Euros and Yen for research. Interna-tional rivalries are growing [12,13]. Political alli-ances are forming and battle lines are beingdrawn. Globally, governments, corporations andventure capitalists spent US$12.4 billion onnanotechnology R&D in 2006, up 13% from2005 [14]. One market report noted that, in2005, nanotechnology was incorporated into

more than US$30 billion worth of manufacturedgoods [15]. This report predicts that by 2014,US$2.6 trillion in global manufactured goodsmay incorporate nanotechnology (∼15% of totaloutput) [15]. Global spending in 2006 on nan-otech products (US$50 billion) far surpassed thatspent on nanotech R&D (US$12 billion) [15]. Arecent study claims that there are over500 nanotechnology-based consumer productsin the marketplace today [102]. It should beemphasized that most market reports or studieson nanotechnology rely on the US NationalNanotechnology Initiative’s (NNI) definition ofnanotechnology (discussed later) to draw theirconclusions. Also, the data reflected in thesereports may sometimes be unreliable. Poorassumptions often underlie the analyses, render-ing the results highly questionable or largelyirrelevant. Therefore, these market reportsshould be taken as indicating general trendsrather than reflecting solid figures.

Flawed patent classification: the result of an inaccurate definitionOne of the problems facing nanotechnology isthe confusion, hype and disagreement amongexperts about its definition [16]. Nanotechnologyis an umbrella term used to define the products,processes and properties at the nano/micro scalethat have resulted from the convergence of thephysical, chemical and life sciences.

One of the most quoted definitions of nanote-chnology is the definition used by the NNI [103]:‘[n]anotechnology is the understanding and con-trol of matter at dimensions of roughly 1 to 100nanometers, where unique phenomena enablenovel applications.’ However, some experts havecautioned against such a rigid definition ofnanotechnology, emphasizing instead the con-tinuum of scale from the nanoscale to the micro-scale [17–22,104]. Clearly, the NNI definitionexcludes numerous devices and materials ofmicrometer dimensions, a scale that is includedwithin the definition of nanotechnology bymany nanoscientists [19–19,21,22].

In fact, various federal agencies are also grap-pling with the definition of nanotechnology.Government agencies, such as the FDA and thePTO, use a definition based on a scale of less than100 nm – a definition essentially copied from theNNI. This definition continues to present diffi-culties, not only for understanding nanopatentstatistics [23], but also for the proper assessment ofnanotechnology’s scientific, legal, environmental,regulatory and ethical [24,25] implications.

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This problem persists because nanotechnologyrepresents a cluster of technologies, each of whichhas different characteristics and applications[17–19,21,22]. The sub-100-nm size range may becritical for a nanophotonic company in whichquantum effects depend on particle size (e.g.,quantum dot size dictates the color of light emit-ted therefrom). However, this size limitation isnot critical to a drug company from a formula-tion, delivery or efficacy perspective because thedesired property (e.g., improved bioavailability,reduced toxicity, lower dose or enhanced solubil-ity) may be achieved in a size range greater than100 nm. Several examples from the pharmaceuti-cal industry highlight this important point (e.g.,Abraxane’s albumin–paclitaxel nanoparticles,Elan Pharma International’s nanoparticles andKereos’s anticancer particles).

To further add to this confusion, expertspoint out that nanotechnology is nothing new.For example, protein vaccines predate the NNI,falling squarely within its definition of nano-technology. In fact, the scale of many biologicalstructures is similar to various ‘nanocompo-nents’. For example, peptides are similar in sizeto quantum dots (∼10 nm) and some viruses arethe same size as some drug-delivery nano-particles (∼100 nm). Hence, most of molecularmedicine and biotechnology can be classified asnanotechnology. I propose a practical definitionof nanotechnology that is unconstrained by anarbitrary size limitation [22]:

‘The design, characterization, production,and application of structures, devices, and sys-tems by controlled manipulation of size andshape at the nanometer scale (atomic, molecular,and macromolecular scale) that produces struc-tures, devices, and systems with at least onenovel/superior characteristic or property.’

Naturally, disagreements over the definitionof nanotechnology carry over to the definitionof nanomedicine. At present, there is no uni-form, internationally accepted definition fornanomedicine either. One definition, uncon-strained by size while correctly emphasizing thatcontrolled manipulation at the nanoscale,results in medical improvements and/or signifi-cant medical changes, comes from the EuropeanScience Foundation [26]:

‘…the science and technology of diagnos-ing, treating and preventing disease and trau-matic injury, of relieving pain, and ofpreserving and improving human health, usingmolecular tools and molecular knowledge ofthe human body.’

Hence, I propose that the size limitationimposed in the NNI’s definition be dropped,especially when it is applied to nanomedicine. Infact, the phrase ‘small technology’ may be moreappropriate here since it accurately encompassesboth nanotechnologies and microtechnologies. Ibelieve an internationally acceptable definitionand nomenclature of nanotechnology should bepromptly developed in this context.

Defining nanomedicine or nanotechnologiesapplied to medicine also has significant ethicalimplications. Definitions help determine thescope of ethical inquiry and define the commonlanguage with which to engage in ethical dis-course. Definitional murkiness for both nano-technology and nanomedicine begs the questionfrom the ethical perspective as to whether nano-medicine presents any new challenges for ethi-cists or whether nanotechnologies applied tohealth and healthcare simply raise old issues in anew light [24,25].

Due to the burgeoning number of new patentapplications filed at the PTO and continued pres-sure from industry, in November 2004, the PTOfinally created a preliminary classification (a cross-reference digest or art collection) for nanotech-nology (designated as Class 977). The purpose ofthis class was described by the PTO on its officialwebsite [105]: ‘[e]stablishing this nanotechnologycross-reference digest is the first step in a multi-phase nanotechnology classification project andwill serve the following purposes, facilitate thesearching of prior art related to nanotechnology,function as a collection of issued US patents andpublished pre-grant patent applications relating tonanotechnology across the technology centers andassist in the development of an expanded, morecomprehensive, nanotechnology cross-referenceart collection classification schedule.’ It is impor-tant to note that this digest should not be con-strued as an exhaustive collection of all patentdocuments that pertain to nanotechnology.

The phrase ‘prior art’ refers to various sourcesof information that the PTO uses to reject a pat-ent application. In other words, it is the ‘knowl-edge’ that exists at the time of the claimedinvention that is used to establish whether or notit is novel. It can include documentary material,such as publications, patents, websites or otherdisclosures, that suggest that the invention is notnew. It can also include evidence of actual uses orsales of the technology within the USA.

The PTO has recently expanded Class 977into numerous subclasses [106]. As of December2006, the PTO has placed approximately 4500

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patents into Class 977. However, these figuresshould only be considered a rough underestimateof the total number of nanopatents. This isbecause the PTO has copied the NNI’s narrowdefinition of nanotechnology for classificationpurposes, which has resulted in a skewed patentclassification system, especially with respect tonanomedicine- and bionanotechnology-relatedinventions. Furthermore, this classificationscheme is neither sufficiently descriptive enoughto accommodate many of the unique propertiesthat nanomedicine inventions exhibit nor does itaddress the interdisciplinary nature and range oftechnologies encompassed by nanomedicine.The PTO’s efforts to provide a home for a fewthousand US patents via a skewed classificationsystem defeats the very purpose for the creationof Class 977, namely:

• To gauge the number of nanotechnologypatent applications filed and patents issued;

• To assist patent practitioners as well as patentexaminers (PTO employees who review patentapplications and grant patents) in searchingnanotechnology patent documents.

Searching nanomedicine prior art: issues & challengesThere are various issues pertaining to nano-medicine patent searching that are of concern. Forexample, some experts state that the PTO lackseffective automation tools to search nanomedicineprior art. Moreover, their databases may not beexhaustive. This problem may be particularly acuteregarding nonpatent prior art. Although there hasbeen a dramatic rise in nanomedicine patent activ-ity, most of the prior art still exists in the form ofjournal publications and book articles. Websitesand pregrant patent publications provide an addi-tional resource. I believe that a large amount of thisnonpatent scientific literature directed at nano-medicine predates many of the nanomedicine pat-ents that have been issued and are currently beingissued. It is possible that patent examiners lackaccess to some of this critical nonpatent informa-tion either because the PTO does not subscribe tothe relevant commercial database or because not allpatent examiners are experienced searchers. As aresult, patent examiners may miss discoveringprior art. The problem of access to nonpatentinformation may not be unique to nanomedicinepatent examination; it is seen in most technologyareas. Furthermore, the internet usage policies ofthe PTO may sometimes prevent patent examinersfrom accessing all relevant databases to retrieve

information. The issue here may be one of securitysince prior art searching on the internet can runthe risk of being tracked externally. Given theseinferior search capabilities, I agree with the conclu-sion that ‘the informational burdens on the exam-iner are clearly heavy – even before the examinerengages in the heavy lifting of interpreting theprior art’ [27].

It seems that patent examiners are often basingdecisions about the grant of nanomedicine pat-ents on limited information. It is frightening toenvision that their faulty decision-making willshape a nascent industry for years to come. It ispossible that this information deficit has ren-dered examination unfocused and inefficient,resulting in the issuance of numerous undulybroad nanomedicine patents (discussed later).

Add to this confused state of affairs the generaldifficulty in searching nanotechnology (or nano-medicine) prior art. Because of its broad andoften overlapping definition, searching andretrieving nanotechnology-related patents andpublications is complicated relative to other tech-nology areas. Different terms can refer to thesame nanomaterial or nanostructure. For exam-ple, ‘nanofibers’, ‘fibrils’ and ‘nanotubes’ havebeen used to describe multiwalled carbon nano-tubes, while ‘single shell nanocylinders’, ‘bucky-tubes’, ‘nanowires’ and ‘nanotubes’ have beenused to describe single-walled carbon nanotubes.Because of this particular point, mapping the pat-ent landscape accurately is also a real challenge.Patents or publications that are truly nanotech-nology based may not use any specific nanore-lated terminology. In fact, patents or publicationsare often written ‘not to be found’ in order tokeep potential competitors at a knowledge disad-vantage. On the other hand, there are business-savvy inventors and assignees who use key wordsincorporating a nano prefix into their patents orpublications to better market their invention orconcept. Therefore, part of the challenge to find-ing ‘true’ nanotechnology (or nanomedicine)prior art is the judicious use of key terms, patentclassification codes and alternative phraseologywhen searching patent and commercial databases.Coupling this strategy with additional filtering bya technology expert is probably the most reliablemethod of uncovering prior art.

A patent law primerGlobally, industries that produce and manage‘knowledge’ and ‘creativity’ have replaced capital,colonies and raw materials as the new wealth ofnations. Property, which has always been the

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essence of capitalism, is increasingly changingfrom tangible to intangible. In fact, intangibleassets as a portion of corporate market capital arealso rising steadily. Intellectual property (IP)rights are a class of assets that accountants callintangible assets. These assets play an ever-increasing role in the development of emergingtechnologies, such as biotechnology, drug devel-opment and nanotechnology. Modern IP con-sists of patents, trademarks, copyrights and tradesecrets. Patents are the most complex, tightlyregulated and expensive form of IP. They havethe attributes of personal property – they may beassigned, bought, sold or licensed.

Patent law is a subtle and esoteric area of lawthat has evolved in response to technologicalchange. It has been modified numerous timessince 1790, the year the first US Patent Act wasenacted. This is due to new interpretations ofexisting laws by the PTO or by the courts and viathe creation of new laws by Congress, often inresponse to new technology. Patent law, arguablyone of the most obscure legal disciplines, is now atthe forefront of nanotechnology. In the new mil-lennium, patent issues are making headlines on adaily basis. As the line between academia andindustry becomes fuzzier, the axiom for success inscience, ‘publish or perish’, is being replaced with‘patent or perish’ or ‘patent and prosper’. Univer-sities are straying from their education mission byfocusing increasingly on patents for potentiallicense revenue. I believe that patents are asimportant, if not more so, as publications on cur-riculum vitae and have a major impact on hiring,tenure and promotion.

The PTO issues three types of patents asdefined by the Statute:

• Utility patents for ‘any new and useful proc-ess, machine, manufacture, or composition ofmatter, or any new and useful improvementthereof ’;

• Plant patents for ‘any distinct and new varietyof plant’ (i.e., asexually reproduced nontuberplant varieties);

• Design patents for ‘any new, original andornamental design for an article of manufac-ture.’ (i.e., ornamental designs of an article ofmanufacture).

Patentable inventions need not be pioneeringbreakthroughs – improvements of existing inven-tions or unique combinations/arrangements ofold formulations may also be patented. In fact, themajority of inventions are improvements on exist-ing technologies. However, not every innovation

is patentable. For example, abstract ideas, laws ofnature, works of art, mathematical algorithms andunique symbols and writings cannot be patented.Works of art and writings, however, may be copy-righted and symbols may be trademarked. Laws ofthe universe or discoveries in the natural world,even if revolutionary, cannot be patented. Forinstance, Einstein’s Law of Relativity cannot beconsidered anyone’s IP.

A US patent provides protection only in theUSA, its territories and its possessions for theterm of the patent. It is estimated that 90% of theworld’s patents are issued through the three mainpatent offices: the USA, Europe and Japan.Legally speaking, a US patent is a documentgranted by the federal government (at the PTO),whereby the recipient (or ‘patentee’) is conferredthe temporary right to exclude others from mak-ing, using, selling, offering for sale or importingthe patented invention into the USA for up to20 years from the filing date. Similarly, if theinvention is a process, then the products made bythat process cannot be imported into the USA.All patented inventions eventually move ‘off ’ pat-ent at the end of their patent term (‘patent expira-tion’), at which time they are dedicated to thepublic domain. This is the basis for low-costgeneric drugs that appear in the marketplace afterexpiration of the costlier versions of the patentedbranded drug.

A patent is not a ‘hunting license’; it is merelya ‘no trespassing fence’ that clearly marks theboundaries of an invention. In other words, apatent grant is a negative grant – it preventsother parties from using the invention withoutprior permission of the patent holder (which canbe in the form of a license). This does not implythat the patent holder can automatically publiclypractice (i.e., commercialize) the invention.Often, appropriate government regulatoryapproval is required.

The basic rationale underlying patent systems,both in the USA and abroad, is simple. An inven-tor is encouraged to apply for a patent by a grantfrom the government of a legal monopoly of lim-ited duration for the invention. This limitedmonopoly or proprietary right justifies R&Dcosts by assuring inventors the ability to deriveeconomic benefit from their work. In exchangefor this grant, the inventor publicly discloses thenew technology that might have otherwiseremained secret (an ‘immediate benefit’ to thepublic) and allows the public to freely use, make,sell or import the invention once the patentexpires (a ‘delayed benefit’ to the public). Hence,

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the new technology that is brought to light in theform of valuable technical information provides acontinuous incentive for future innovation. Inthis way, society obtains a quid pro quo frominventors in exchange for the temporary grant ofexclusive rights. Such an advantageous exchangestimulates commerce (a ‘long-term benefit’ to thepublic). Patent protection is the engine thatdrives industry and the incentive for it to investin R&D to innovate. Clearly, without such pro-tection, most big companies would avoid costlyR&D and society would be deprived of the manybenefits thereof. However, it is critical that thescope or breadth of the patent issued by the PTObe just right; it should neither be unduly broadnor should it be too limiting. In other words, theinvention that is granted a patent should just fitwithin the boundaries of that patent.

For a US patent to be granted, an inventionmust meet all of the following criteria set forthin Statutes:

• It must be novel (i.e., sufficiently new andunlike anything that has been patented, mar-keted, practiced, publicized or publishedpreviously);

• It must be nonobvious to a person with knowl-edge in the field related to the invention,meaning that the person would not automati-cally arrive at the present invention from areview of existing ones (i.e., trivial variationsthat are readily apparent to a person withknowledge in the field related to the inventioncannot be patented);

• It must have utility (i.e., the invention hassome use and actually works or accomplishes auseful task);

• It must be described adequately to the publicin order to demonstrate ‘possession’ of theinvention at the time of filing;

• It must enable a person with knowledge in thefield related to the invention to make or carryout the invention without ‘undue experimen-tation’ (i.e., to make the claimed product orcarry out the claimed process without unduetrial and error);

• It must enable a person with knowledge inthe field related to the invention to use theinvention;

• It must be described in clear, unambiguousand definite terms;

• It must set forth the best mode of making andusing the invention contemplated by the inven-tor at the time of filing the patent application;

Obtaining a patent for an invention is often along, expensive and tedious process that generallyinvolves the inventor, patent counsel or practi-tioner (i.e., patent agent or patent attorney) andPTO staff (especially a ‘patent examiner’). Patentexaminers are PTO personnel who review thefiled patent application to ensure that it fulfils allpertinent requirements of the law listed above.This review process is commonly referred to as an‘examination’. The exchange of documentsbetween the PTO and the patent counsel isbroadly known as ‘prosecution’. If the examinerbelieves that all requirements for a patent are met,then a ‘notice of allowance’ is issued to the appli-cant. Finally, a patent is issued once the applicantpays an ‘issue fee’. Following this, the entire con-tents of the patent application (‘the file wrapper’or ‘prosecution history’) along with a copy of theissued patent and all future documents pertain-ing to the patent are made available to the pub-lic. Since the granting of the first US patent in1790, more than 7 million patents have beenissued by the PTO. In fact, 1790 was the firstyear of operation for the PTO and it issued onlythree patents. On the other hand, in the 2006fiscal year (October 1, 2005–September 30,2006), 183,187 patents were issued. For the pastfew years, the PTO has received over 400,000patent applications annually. In the 2006 fiscalyear, the average patent pendency ranged from25.4 to 44 months. The number of patent appli-cations filed since 1996 has been increasing, onaverage, by over 10% per year.

As part of patent prosecution, all applica-tions filed on or after November 29, 1999, arepublished 18 months after filing (up to thatpoint they are kept confidential), unless theapplicant opts out and foregoes foreign filing.This implies that, generally, a patent applica-tion as filed will eventually appear in the publicdomain (whether or not it is patented) and willbe available to competitors. The entire patentexamination process, starting with the filing ofthe patent application to its final allowance orfinal rejection, may take anywhere from 1 to5 years or longer. This depends upon severalvariables, such as the specific technology areawithin the PTO where the patent is beingreviewed by the patent examiner and the timeto process the paper-work that accompanies thepatent application by the PTO clerical staff.

Since the patent term commences from thedate of filing and ends after 20 years, most com-mercially valuable nanomedicine inventions are,in reality, in the marketplace prior to the actual

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patent grant date (unless regulatory approval issought). Generally, it is impossible to predictthe future commercial success or commercialviability of an issued patent. In part, this isowing to the fact that most patents are filed atthe PTO without any clear idea of whether theinvention is commercially valuable. For exam-ple, in nanomedicine, patent applications arecontinuously being filed on a large number ofdrugs, therapies and devices, even before it isknown that they will be ruled safe and effectiveby the FDA. If litigation rates (which rangefrom 1.5 to 2% of the issued patents) are anyindicator of commercial value, then only a frac-tion of patents are commercially significant.Although obtaining a patent does not ensurecommercial success, economists view patentingas an indicator of scientific activity. They arguethat this is the basis for providing a nation witha competitive advantage, fueling its economy.

In recent years, however, patents have becomethe subject of much debate and controversy. Infact, there are plenty of antipatent players in thefield who feel that patent laws (and most inter-national treaties) are unfairly providing an eco-nomic advantage to some over others. It haseven been suggested that patent laws and IP arethe products of a new form of western colonial-ism designed to deny the developing worldaccess to common goods. Issues such asbiopiracy, IP theft and greed on the part of mul-tinationals have been proffered as reasons for theunavailability of essential drugs to the poorestand neediest people in the world. Not surpris-ingly, those in the developing world supportpatent protection but prefer a regime that suitstheir own national interests. In this regard, theyhighlight the fact that, although western drugcompanies continue to cite the need to rewardinnovation as a justification for stronger patentlaws or patent enforcement, the industry con-tinues to spent more on reformulating pre-exist-ing drugs and on expensive litigation to protecttheir current patent portfolios than to innovate[28]. Future struggles over patents on the interna-tional stage are almost certain to focus on drugpatents where multinational drug patents arerevoked or challenged [29]. In my view, a multi-national drug company’s patent rights and pro-viding access to affordable drugs to thedeveloping world are inter-related; they shouldnever be considered mutually exclusive.

Note that the PTO does not police or monitorpatent infringement nor does it enforce issuedpatents against potential infringers. It is solely up

to the patentee to protect or enforce the patent,all at the patentee’s cost. The patentee may enlistthe US government’s help via the court system toprevent patent infringement. PTO decisions aresubject to review by the courts, including theCourt of Appeals for the Federal Circuit (CAFC)and, rarely, the US Supreme Court. SometimesCongress intervenes and changes or modifiessome of the laws governing patents.

The CAFC was created by Congress in 1982with the aim of creating uniformity in patentlaw, especially with respect to unpredictable,evolving technologies, such as biotechnology andnanotechnology. In reality, it has sometimesfailed in this role by rendering inconsistent andcontradictory patent decisions.

If a court deems a patent to be invalid, thepatent holder is unable to enforce it against anyparty. However, suing an alleged infringer is arisky business. When a patent holder sues analleged infringer, in certain technologies, there isa 50% risk that the patent holder’s own patentwill be found invalid.

Based on my review of seminal CAFC patentdecisions from the past decade or so, it is myfirm conclusion that the CAFC has fosteredthe following:

• Expanded what can be patented under thepatent statutes

• Lowered the threshold to obtain a US patent

• Tilted its decisions in favor of patent holders

Clearly, this stance has resulted in stronger pat-ent protections for patent holders. As a result,since the creation of the CAFC, the number ofpatents granted has increased at an annual rate of5.7%, compared with less than 1% from 1930 to1982 [30]. According to some experts, if this trendcontinues, it could stifle competition and limitaccess to some inventions. Moreover, this is con-trary to the quid pro quo discussed earlier: it dis-turbs the delicate balance between the patentholder’s limited-time monopoly on the inventionon one hand and the public’s interest in accessingthe invention (from the public domain) on theother. Certainly, this could be the very reason whythe Supreme Court is increasingly stepping in tohear more and more patent appeals of CAFCdecisions. It is important to note that theSupreme Court, which has rarely reviewed patentdecisions in the past, has heard seven importantpatent appeals of CAFC decisions in the past4 years alone, reversing each one of them. One ofthese recent landmark rulings [31] broadly impactsnanomedicine. It allows drug companies to

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infringe drug patents held by others as long as theinfringement is during the R&D phase (i.e., pre-clinical phase) of drug development and generatesdata (on the compound being tested) that may (ormay not) be ultimately submitted to the FDA aspart of the drug-approval process. Another recentSupreme Court ruling may make patenting newinventions and defending existing patents muchmore difficult in all technologies [32].

By these and other recent decisions, theSupreme Court may be trying to re-establish thebalance between the patent holder and the pub-lic’s interest, a certain flexibility that it may haveviewed as eroding under the CAFC. It is criticalthat the CAFC refocus its efforts to providegreater clarity to patent law and render patentdecisions that are more consistent. After all, thisis its true mission.

One highly controversial yet important statisticworth briefly discussing is the patent allowance orgrant rate (percentage of applications reviewed byexaminers that are approved). Several legal schol-ars have published studies to gauge this figure.One widely cited estimate places the average PTOgrant rate at 77–95% of filed patent applicationsfor the years 1981–2005 [33]. However, I agreewith some legal scholars who consider this esti-mate to be artificially high, since it may be basedon an inappropriate legal framework and some-what flawed numbers [34]. In any case, the exactfigures are immaterial; the crux of the matter isthat the PTO grant rates are high and this mayindirectly reflect a less rigorous review of patentapplications compared with the other major pat-ent offices. In other words, these high allowancerates may be partly to blame for the granting ofpoor-quality patents (other concerns aredescribed later). In this context, it is interesting tonote that the time taken for 1 million patents tobe granted has greatly declined since the grant ofUS Patent No. 1 in 1836 (the first US patent wasissued in 1790 while the numbering system wasdeveloped in 1836).

In light of this discussion about patent allow-ance rates and patent quality, it is rather interest-ing to note the PTO’s recent announcement of a54% allowance rate for the past fiscal year. Inthis regard, it is further worth noting that,although the number of patent applications hascontinued to increase, creating a steady backlogthat threatens businesses (according to PTO’sown estimate, at the end of 2006, there weremore than 700,000 unexamined patent applica-tions), the number of issued patents hasdeclined in recent years. The most notable

decline was in 2005, when a drop of 11% in theallowance rate was reported from the previousfiscal year. What does this mean? Do these fig-ures imply a vast improvement in patent qualityover the earlier years when allowance rates weremuch higher? Most experts would disagree. Ifthis is not the case, then is it possible thatnumerous high-profile patent cases and blun-ders (like the recent BlackBerry case) have over-sensitized PTO upper management, who arenow actively engaged in artificially suppressingthe high patent grant rate? Is the PTO trying topaint a rosy picture of improvement in patentquality? Some commentators are perplexed atthis drastic dip in allowance rate, given that allindications are that ‘inventive quality should berising, not falling’ [35]. Tinkering with the patentsystem can have disastrous consequences for theentire innovation process. Moreover, it is clearlycounter to the basic tenet of the US patent sys-tem: ‘[t]o promote the Progress of Science andUseful Arts’ [36].

Significance of patents: the fuel for the ‘nanomedicine revolution’Patents are critical to the nanomedicine ‘revolu-tion’. When investors in nanomedicine or drugcompanies consider the merits of their invest-ment, patent issues are one of the most impor-tant items they review. There is also ampleevidence that companies, start-ups and universi-ties are ascribing ever greater value and impor-tance to patents. Increasingly, they are willing torisk a larger part of their budgets to acquire anddefend patents. The process of converting basicresearch in nanomedicine into commercially via-ble products is proving to be long and difficult.The development of nanomedicine-related tech-nologies is extremely research intensive andwithout the market exclusivity offered by a pat-ent, development of these products and theircommercial viability in the marketplace wouldbe significantly hampered.

Patents are especially important for start-upsand smaller companies because they may help innegotiations over infringement during competitiveposturing with larger corporations. Often largecompetitors employ frivolous suits to pressure asmaller company or start-up whose patentstands in their way, or which they wish toacquire. Patents may also protect the clients of apatent owner because they prevent a competitorfrom infringing or replicating the client’s prod-ucts made under license from the patentee.Moreover, patents provide inventors credibility

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with their backers, shareholders or venture capi-talists – groups who may not fully understandthe science behind the technology. Generally,patents precede funding from a venture capitalfirm. For a start-up company, patents are notonly a means of attracting investment but alsoserve to validate the company’s foundationaltechnology. Therefore, start-up companiesaggressively seek patents as a source of signifi-cant revenue. They cite the potential for licens-ing patents and the power to control emergingsectors of nanotechnology as major reasons forseeking patents [23]. Moreover, venture capital-ists are hesitant to support a start-up that relieson trade secrets alone. In summary, investors areunlikely to invest in a start-up that has failed toconstruct adequate defenses around its IP viavalid, enforceable patents.

A company seeking a dominant position in aparticular sector of nanomedicine may wish toreview patent citations (i.e., patents cited inother patents). Patent citations can serve as auseful indictor of licensing potential: patentsthat are cited repeatedly are generally consideredmore commercially valuable. A quarter of allpatents receive no citations at all, whereas a mere0.01% earn greater than 100 citations [37].According to one study, a patent cited 14 timeson other patents is, on average, 100-times morevaluable than a patent cited only eight times [37].

Millions of dollars may be lost if a companyfails to take the necessary steps to protect its pat-ent assets. Securing valid, defensible patent pro-tection is vital to the long-term viability ofvirtually any drug or biotechnology company,whether or not nanotechnology is involved in theplatform technology. Often, loss of these criticalassets is a result of both the researcher’s excite-ment with his or her research as well as generalignorance about IP. In fact, experts agree that‘patent awareness’ (i.e., the knowledge that pat-ents are intangible property that can be obtainedand lost) is central to any business plan or strat-egy [38]. Furthermore, it is essential that managersand patent practitioners implement certainproactive measures to ‘box out’ the competition[18]. In other words, taking the correct preventivesteps is critical to realizing the full commercialpotential of an invention [18]. Because nanomedi-cine interfaces with fields, such as biology, phys-ics, chemistry, engineering, medicine andcomputer science, filing a patent application (orconducting a patent search) in this field mayrequire expertise in these diverse disciplines.Hence, employing a qualified patent counsel (a

patent agent, a patent attorney or a multidiscipli-nary team of lawyers) who understands the legaland technical complexities is a critical step inobtaining quality patents. Additionally, issuedpatents and other prior art should be evaluatedcarefully and effective patent-drafting strategiesdevised accordingly.

The phrases ‘patent value’ and ‘patent qual-ity’ are important, yet distinct concepts. Butthey are somewhat related and largely deter-mine a patent’s potential for commercialization,licensing opportunities, investor interest andenforceability. They are briefly discussed below.

The ‘patent value’ of an issued nanomedicinepatent is often measured in terms of other factors(‘valuation metrics’):

• The breadth and scope of the claims of theissued patent that affect competitors’ freedom-to-operate (this correlates with the patent’soriginality);

• The number of potential competitors in thatparticular sector of nanomedicine;

• Government fees (‘maintenance fees’) paid tokeep the patent enforceable;

• The patent’s applicability to other fields;• Licensing and litigation activity surrounding

the patent;• The frequency by which that patent is cited by

others (discussed earlier);• Other IP held by the patent-holder in that

particular technology, including any blocking,pioneering or upstream patents.

‘Patent quality’ generally refers to the ability ofa patent examiner to make proper, timely deci-sions about the validity and scope of protectionduring the examination process that is consistentwith the legal ruling a court would make aftercomprehensive review of the same application.

Last year, the PTO proposed several changesin patent practice that could significantly alterthe way in which nanomedicine companies fileand prosecute patent applications [39,40]. There-fore, companies may need to rethink their patentstrategies to maximize their patent rights, includ-ing taking appropriate proactive action on pend-ing patent applications prior to the actualimplementation of these new rules.

Patenting nanoformulations: the example of solid drug nanoparticlesNanoformulating existing drugsNanomedicine is already impacting the drug-delivery arena. Drug companies now recognizethat DDSs must be an integral part of their

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R&D process at an early stage. According to onemarket report, nanotechnology-enabled DDSswill generate over US$1.7 billion in 2009 andover US$4.8 billion in 2012 [107]. This reportprojects that the global drug-delivery productsand services market will surpass US$67 billionin 2009 [107]. Another report placed the nano-technology-enabled drug-delivery market for2005 at approximately US$1.25 billion, grow-ing to US$5.25 billion by 2010 andUS$14 billion by 2015 [41].

Current US patent laws allow the grant ofpatents on new drug formulations that havebeen created from old drugs (e.g., via novelDDSs). Nanotechnology could also allowreformulation of existing and/or orphanedcompounds. These new reformulations mayqualify as NCEs at the FDA and for patents atthe PTO. In other words, ‘nanoformulations’of older drugs may be patentable as long as theyfulfill all the criteria for patentability men-tioned earlier (see the ‘A patent law primer’ sec-tion). Furthermore, innovative DDSs orplatforms may be patented on their own undercurrent US patent statutes. Innovative DDSscould enable drug companies to devise noveldrug reformulations of off-patent or soon-to-beoff-patent compounds. This strategy coulddelay or discourage generic competition duringthe most profitable years of an innovator drug’slife cycle. This is especially true if the reformu-lated drug is superior to its off-patent or soon-to-be off-patent counterpart. In effect, thisapproach stretches the product lifecycle of anexisting, branded, patented drug. This strategy,commonly referred to as ‘product-line-exten-sion’ or ‘patent evergreening’, is broad in scopeand includes any second-generation adaptationof an existing drug that offers improved safety,efficacy or patient compliance [42]. In fact,reformulation strategies should focus on howto add value through added ease and conven-ience for the consumer. If this approach is suc-cessful, the innovator of the DDSs or platformscan maintain market share even after genericsappear in the marketplace.

There are a number of DDSs, platforms orpolymer-carrier systems available that can beadapted to various drugs in an effort to reformu-late them to generate improvements with respectto delivery method, dosage form or dosagestrength. Improvements may also be created byconjugating, entrapping or modifying the drugitself to create a superior product (e.g., by creat-ing poly[ethylene glycol] [PEG]-coated versions

or reformulating it with a new salt or ester).Another often-employed approach is to developand patent a novel polymorph of the innovator’sdrug compound prior to patent expiration. Yetanother strategy involves generating patent pro-tection on a competitor’s formulation (patentedor off-patent) by analyzing the competitor’sexisting patent claims, then tweaking them andfiling patents that circumvent the competitor’sspecific use or DDS.

All of these approaches could lead to poten-tially patentable drug versions with stable reve-nue streams. Obviously, it is important to havephysicians and healthcare professionals switchto the new and improved (re)formulations sothat market position is not lost to generic com-petition. Switching a branded drug, wheneverfeasible, to over-the-counter status (the so-called ‘Rx-to-OTC switch’) is another strategythat can extend the life of the branded formul-ation. Moreover, this approach almost alwaysimproves sales figures, especially if the FDAgrants Hatch-Waxman 3-year exclusivity.According to one estimate, a single year ofextended patent protection generates approxi-mately 18% of the average product’s sales vol-ume [43]. Some experts estimate that, today,generics may take 80–90% of market sharewithin the first few weeks of entering the mar-ketplace [42]. The first generic to enter the mar-ket following patent expiration is generallypriced 30–40% lower than brand names andthis figure can further drop to 80% lowerwithin 2 years of patent expiration [43].

Reformulations are generally considered tocreate a disproportionate amount of value giventheir cost [44]. According to a 2004 report,reformulations in the drug industry will growfrom 62% of the total drug market in 2003 to79% in 2008 [44]. However, it is worth men-tioning here that branded drug patents, espe-cially those directed to reformulations, arecoming under relentless legal attack by propo-nents of generics who view them as stretchingthe limits of what deserves a new patent.Clearly, it is the multibillion dollar sales figuresof these blockbusters that encourage genericand other drug companies to aggressively attackthe validity of such patents.

Patenting solid nanoparticulate drugsSolid nanoparticles are colloidal particles of size 1to 1000 nm (1 µm) that are useful as drug-deliv-ery platforms [45,46]. They have become an impor-tant area of research in DDSs owing to their

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ability to deliver a variety of active pharmaceuticalagents to different sites within the body for a pro-longed period. Nanoparticle size and surfaceproperties dictate their in vivo behavior. Specifi-cally, these properties permit systemic circulationand determine nanoparticulate biodistributionwithin the human body. It is this size that impartsthem with unique properties in contrast to largerparticles. Their smaller size allows them access toplaces in the human body that larger particlescannot reach.

Particle size has an impact in another way too.The efficiency of drug distribution within vari-ous body cavities is influenced, in part, by thesize of the drug particles. As the particle size of adrug decreases, its total surface area increasesexponentially [47]. This reduction in particle sizeincreases its dissolution rate and saturation solu-bility, which frequently correlates with improvedin vivo drug performance [48,49]. In some cases,the pharmacokinetic behavior of nanoparticledrugs may help minimize peak plasma levels(which may be toxic) as well as prevent a dropbelow the targeted therapeutic range (which maylower efficacy). In fact, many drug companies arerevisiting shelved drugs that were ‘difficult’ froma formulation point-of-view due to their solubil-ity profiles. They are starting to rely on nano-technology companies to address theformulation challenges of their drugs.

It should be pointed out that reformulation ofan existing drug into a nanoparticulate versiongenerally results in a novel NCE because it oftendisplays an altered pharmacokinetic profile(altered AUC and Cmax) compared with its parent(larger/bulk) counterpart. In other words, nano-particulate drugs are generally not bioequivalentto their parent (larger/bulk) counterparts. Hence,drug companies cannot apply for FDA approvalvia an Abbreviated New Drug Application(ANDA) route reserved for generic drugs. How-ever, if the nanoparticulate formulation isbioequivalent to its parent (larger/bulk) version(meaning the dissolution rate and absorption issimilar), an ANDA can be filed to seek regulatoryapproval. Under the Hatch Waxman Act, theFDA approval process for NCEs benefits theinnovator in two ways:

• The new drug enjoys a 3–5-year nonpatentexclusivity period that prevents generics fromentering the marketplace;

• The patent owner can recover some of the pat-ent term lost because of the delay caused bythe FDA regulatory review process.

If the nanoparticulate drug is being tested onchildren, there is a FDA provision that extendspatent protection by 6 months (known as the‘pediatric rule’).

Although there are few widely marketed solidnanoparticle formulations, numerous nano-medicine-related products are either underdevelopment or nearing commercialization[1,11,18,19,21,46,47,50–52]. This is an obvious conse-quence of the extremely complex and demandingrequirements of clinical trials by the FDA. How-ever, based on their ability to reduce time to mar-ket, extend the economic life of proprietary drugsand create additional revenue streams, nanoparti-cle-based drugs will impact the drug commerciali-zation landscape significantly in the near future. Inthe process, they will become an integral part ofmainstream medicine, offering consumer-friendlyproducts. As the drug industry increasingly beginsto adopt them, nanoparticle-based DDSs are likelyto be among the first products to generate seriouspatent battles and cross-licensing activity (which isan exchange of roughly symmetric patent positionsbetween two or more parties) [53].

It is yet to be seen if nanoparticle patent appli-cations will face the same patent hurdles thate-commerce and some biotechnology patentapplications faced. These patent applications wereinitially held to be nonpatentable. In any case,nanoparticle-based drug formulations, as withother nanoscale inventions, are patentable so longas they satisfy the patent requirements discussedearlier (see the ‘A patent law primer’ section). Sizealone is not a criterion for patentability in theUSA; the mere fact that the device or processinvolves a change in scale does not allow for thegranting of a patent. In fact, it is a well-establishedlegal doctrine that limitations relating to the sizeof a claimed structure, device or process are notsufficient to distinguish over the prior art – themere scaling up or down over the prior art doesnot by itself establish patentability [54,55]. TheCAFC has held that when size is the only differ-ence between the claimed device and the prior artdevice and a device having the claimed relativedimensions would not perform differently thanthe prior art device, the claimed device is not pat-entable [56]. However, a nanoscale invention maybe patentable if it performs a new function, unlessthe function can be performed by other methods.Even this hurdle may be overcome by the inventorif he or she can demonstrate that the nanoscaleinvention’s function involves an improvementover the prior art and is not obvious to a ‘worker’in that particular scientific field or technology.

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Typically, when patenting new formulations ofpreviously known drugs, the biggest hurdle isestablishing nonobviousness. The PTO often takesthe initial position that new drug formulations aremere ‘optimizations’ and, hence, are not patenta-ble. This particularly holds true where the ingredi-ents in the formulation have been used previouslyin other formulations, especially with recognizedeffects or benefits. To establish that a particularformulation is nonobvious, it is often necessary forthe applicant to convince the patent examiner thatthe formulation has some unexpected superiorproperty or provides an improvement, such asreduced toxicity, enhanced bioavailability, altereddrug stability, solubility or activity. Showing suchan unexpected property often requires submissionof experimental data during prosecution of thepatent application, comparing the inventive for-mulation with the closest formulation previouslyknown. In this manner, the applicant can rebutthe initial position of the PTO and establish thathis or her formulation is indeed inventive andtherefore, entitled to a patent. Because the nano-particulate drug prior art is still relatively imma-ture and because nanoparticle properties areoften unpredictable, it may be easier for aninventor to establish unexpected properties fornanoparticulate drugs over traditional drug for-mulations and obtain a patent. However, thispatenting trend will eventually change as moreand more nanoparticulate drug prior art accu-mulates and more judicial opinions on patentsinvolving nanotechnology emerge.

Nanomedicine patent proliferation & PTO problems: a recipe for disasterFederal agencies continue to grapple over nan-otechnology issues. The PTO is no exception.In fact, for more than a decade, all of theworld’s major patent offices have faced anonslaught of nanomedicine-related patentapplications [13,15,17,18,57–62,108]. The situation atthe PTO is likely to worsen as more applicationsare filed and pendency rates further skyrocket. Ascompanies develop products and processes andbegin to seek commercial applications for theirinventions, securing valid and defensible patentprotection will be vital to their long-term sur-vival. In the decades to come, with nanomedicinefurther maturing and promised breakthroughsaccruing, patents will generate licensing revenue,provide leverage in deals and mergers and reducethe likelihood of infringement. The developmentof nanomedicine-related products, which isextremely research intensive, will be hampered

significantly in the absence of the market exclu-sivity offered by a patent. Due to the PTO’s dis-mal handling of critical problems such as poorexamination quality, skyrocketing patent pen-dency, out-of-control examiner attrition, andpoor work force morale I discuss below some ofthe more pressing issues with respect to ‘patentsand nanomedicine’.

A chaotic nanotech patent land grab continues Because of the potential market value of nano-medicine products, every player in the interna-tional race for technological dominance –researchers, executives and patent practitioners –view the collection and exploitation of nano-medicine patents as critical. In fact, these playersare making an effort to obtain the broadest pro-tection possible for new nanoscale polymers,devices and systems that have applications inbiotechnology and medicine. Therefore, a sort of‘patent land grab’ (Figure 1A–C) is in full swing by‘patent prospectors’ as start-ups and corporationscompete to secure broad patents in nano-medicine during these critical early days[18,19,21,22,59–62]. This land grab mentality is fur-ther fueled by the relative lack of products andprocesses in the marketplace. Companies feelthat, to demonstrate confidence and sway ven-ture capitalists, they must generate or claim IP.Some companies also feel pushed into claimingas much IP as possible. They fear that if they lagbehind in this effort, someone else will claim thebroadest IP. Similarly, academic researchers feelcompelled to file patents in order to bolster theirreputation and curriculum vitae. Moreover, mostinventors have quickly realized the opportunitiesavailable at a disorganized PTO during theseearly days of nanomedicine for securing broadpatents on valuable upstream technologies withrelative ease.

With nanotechnology maturing further, thenumber of claims in patent applications and theamount of scientific literature cited during pat-ent prosecution is on the rise (Figure 2). The latteris significant because scientific publications arethe most accurate indicator of scientific activityand productivity. Another trend observed is thatnanotechnology patent owners are eyeing com-mercial potential and therefore maintainingmore of their patents (Figure 3). All issued utilitypatents are subject to the payment of mainte-nance fees to the PTO to maintain them inforce. Failure to pay a maintenance fee on timewill result in the expiration of the patent.

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Figure 1. Growth of

(A) US nanotechnology ppatents issued. (C) Risingin nanotechnology.Data reflected in all figurInitiative’s definition of ntrends and not exact num

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However, these patent prospectors have to dealwith an overburdened PTO, which historicallyhas been slow to react to emerging technologies,such as biotechnology and software. In fact, theentire US patent system is under enormous scru-tiny and strain as the PTO continues to strugglewith the evaluation of nanomedicine-related pat-ent applications. Commentators are increasinglyvoicing their concerns regarding emerging nan-otechnology patent thickets and their impact onglobal access to products [63]:

“Although industry analysts assert that nan-otech is in its infancy, ‘patent thickets’ on funda-mental nanoscale materials, building blocks andtools are already creating thorny barriers for

would-be innovators. Industry analysts warnthat IP roadblocks could severely retard thedevelopment of nanotechnology. Some insistthat nanoscale technologies will address the mostpressing needs of the [world’s] marginalized peo-ples. But, in a world dominated by proprietaryscience, it is the patent owners and those whocan pay license fees who will determine accessand price … The world’s largest transnationals,leading academic labs and nanotech start-ups areall racing in the patent gold rush. Increasingly,universities are licensing on an exclusivebasis … Control and ownership of nanotechnol-ogy is a vital issue for all governments and civilsociety because nanomaterials and processes canbe applied to virtually any manufactured goodacross all industry sectors … At stake is controlover innovations that span multiple industrysectors … companies that hold pioneering pat-ents could potentially put up tolls on entireindustries.”

In fact, some of the concerns highlighted aboveare borne out by US nanotechnology patentdemographics from 2006 (Figure 4).

Problems plague the examination process Although the PTO budget has bloated to it’scurrent US$1.6 billion, various examinationproblems continue to haunt it. One patentexpert recently summarized the current crisis atthe PTO [64]:

“The US Patent and Trademark Office isunder siege for issuing patents that should neverhave issued, and for excessive delays. Congress isconsidering changes such as a new oppositionsystem for challenging patents when theyemerge from examination…”

A law Professor is blunter in her criticism [109]:“The United States patent system is broken anddesperately needs fixing … Why are so many badpatents being issued? … Under our current sys-tem, granting an application with little scrutinytakes less time than subjecting it to rigorousreview … The examiners are unable to performmore than a cursory search of their own [due totime constraints] … Third parties – competitorsand consumers – are generally excluded from thepatent examination process, even though theseparties have the greatest incentive to discover theprior art and disclose it to the Patent Office inorder to prevent bad patents from being issued…”

Indeed, questionable patent examinationpractices at the PTO seem to extend acrossother technology areas. Although efforts areunderway to improve the quality and efficiency

the nanotechnology knowledge base.

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Figure 2. Trends in ncited references.

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of the patent examination process generally, var-ious shortcomings continue to beset patentexamination. Some of the problems that impactnanomedicine are examined briefly below.

• At present, the agency lacks a dedicated exam-ining group (so-called ‘Technology Center’[TC]) to handle nanomedicine or nanotech-nology applications. Although the formationof a separate TC may be premature, I suggestcreating a working group or committee withineach TC that identifies nanotechnology patentapplications as they are filed, formulates exam-ination guidelines, undertakes training ofselected examiners and periodically meets withits counterparts from other TCs. This is espe-cially critical because only a few examinershave experience in this rapidly evolving field.Because nanomedicine is interdisciplinary innature, patent applications that are searched,examined and prosecuted in one TC could andshould be examined more effectively via a

coordinated review by more than one TC. Inreality, there is no collective review and, as aresult, applications continue to be examineddifferently within each TC. Obviously, such anapproach does not provide a consistent anduniform examination of applications becauseexaminers in different TCs may rely on caselaw, legal standards and prior art that may besomewhat unique to their own TC;

• Many nanomedicine patent applications maynot receive adequate examination during pros-ecution because of the patent examiner’s ina-bility to locate applicable prior art, especiallynonpatent prior art. Therefore, as discussed indetail earlier, it is accurate to conclude thatpatent examiners may sometimes be makingdecisions about the grant of a nanomedicinepatent on limited information;

• The PTO continues to be understaffed innumerous TCs and it is plagued by high attri-tion. The agency’s inability to attract and retaina talented pool of patent examiners is creatinghavoc. At hearings on Capitol Hill and in itsannual reports, the PTO brass proudly touts hir-ing hundreds of new patent examiners each fis-cal year to alleviate the backlog problem that isclogging the patent system. In fact, in this con-text, the Commissioner for Patents continues tohighlight that the PTO will hire 1200 new pat-ent examiners in the current fiscal year [65].However, the PTO brass fails to focus on thecritical issue of ‘brain drain’ resulting from anexodus of so many experienced patent examin-ers (and other senior-level executives). It wouldbe wise for PTO upper management to focuson retaining more of its experienced employeesand not putting all its efforts into hiring newones. These attrition rates are likely to be fur-ther exacerbated by decreasing morale and gen-erally poor work conditions. Moreover, manyreports have highlighted the fact that the federalgovernment is vulnerable to ‘brain drain’ bothbecause baby boomers are retiring and becausetheir potential replacements (most notablygraduate students) do not view the governmentas their first choice of work [65]. According tomany experts, patent examiners are underpaid(relative to US law firm salaries) and overworked(compared with their colleagues at the EuropeanPatent Office). They also have to review applica-tions under unreasonable time pressures andskyrocketing patent pendency (discussed later).Arguably, the internal quality review processthat monitors the quality of patents that have

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been allowed by patent examiners is fraughtwith a general lack of legal and scientificexpertise on the part of the reviewers;

• The PTO’s funding problems are legendary.Congress’s long-standing practice of ‘diverting’PTO user fees collected from patent applicantsto the general federal budget has always causedmuch consternation. Naturally, stopping thispractice would alleviate some problems at theagency. In February 2007, a bill was signed bythe President that allows the PTO to spend allits projected collected fees, thereby preventingfunds from being diverted to other governmentprograms. Hopefully, as a result of this law, thedamaging drain on the agency’s financialresources will finally come to an end. I alsohope that the PTO will now temper its annualpractice of hiking patent fees;

• Even today, with all the quality initiatives under-way, examiners are still largely rewarded on thequantity of their work, not the quality. An anti-quated quota system is in place. The patentexaminer’s production goals (quota) have notbeen adjusted in decades in spite of the increasedcomplexity of patent applications filed, not tomention the substantial increase in the amountof prior art that the examiner has to search andanalyze. Quality continues to take a back seat toquantity. Although, reading PTO annual reportsor press releases would lead one to believe that allis perfectly well in this regard. According torecent PTO statistics, the allowance error ratehas hovered around 4%. This could imply thatthe PTO’s own conservative estimates indicatethat thousands of US patents were ‘wrongly’allowed [35];

• The PTO has failed to effectively engage out-side legal or technology experts. Only a hand-ful of experts from industry or academia have

lectured on legal or technical issues unique tonanomedicine. This reluctance to use outsideexpertise has further added to the informa-tion deficit in nanomedicine. It is clear thatthe PTO lacks internal expertise in these mat-ters and its isolationist policy only com-pounds the problem. Moreover, patentexaminers are not required to have advanceddegrees in science or engineering. Possessingadvanced degrees or advanced training, byand large, goes unrecognized at the PTO;

• Few training modules or examination guide-lines have been developed to educate patentexaminers about the complexities and sub-tleties of nanomedicine. Similarly, no writ-ten guidelines specific to nanomedicine areavailable for patent practitioners.

Given all these challenges, it is hard to predicthow these issues and challenges will play outwith respect to nanomedicine patenting or com-mercialization. We will have to wait and seewhether the nanomedicine industry thrives, likethe information technology industry, or becomesburdened, like the radio patent deadlock [62].

Congress is continuing patent reform hearingsin an effort to eliminate questionable patents aswell as to provide adequate safeguards againstabuses to the patent system. In fact, patent-reform bills are currently pending in bothHouses of Congress. Similar measures in the past2 years have failed as the information technologyindustry and big pharma battled over the finerpoints of the bills. However, it appears that thelong-sought reform bill will finally be passed byCongress this year.

One of the proposals under serious considera-tion is a so-called ‘post-grant review’ of patentapplications. However, I agree with some patentveterans that ‘[s]erious doubts exist whether apolitically controlled PTO can guarantee thepromise of the post-grant system that the patentcommunity so desperately needs … [T]he patentcommunity can hardly have confidence in a post-grant review system under the control of thePTO…’ [110].

The nanotech patent onslaught tests the PTOFor the past decade or so, there has been a dra-matic increase in the number of new nanotech-nology patent applications filed and patentsgranted (Figures 1A & B), as well as an increase inpublished patent applications and scientific pub-lications (Figure 1C). This information overload

ology patent demographics.

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has created numerous challenges for the PTO, anagency that traditionally struggles with this issue.Furthermore, this overburdened agency has yetto implement a solid plan to handle the enor-mous growth in nanotechnology patent applica-tions filed. This has resulted in added time toreview patent applications (i.e., an increase inpatent pendency) and concerns about the valid-ity and enforceability of numerous issued patents(reflects a decrease in patent quality).

The backlog of nanotechnology patent appli-cations continues to build. A recent report putsthe average nanotechnology patent pendency at4 years (Figure 5) [15], a period that is simply toolong for certain nanotechnologies that peak andare then obsolete in a few years. This excessivedelay has serious business consequences, partic-ularly for smaller companies and start-upsbecause these entities rely heavily on venturefunds for their success. Therefore, it was no sur-prise that they recently confronted the Under-secretary of Commerce regarding the highpatent pendency of their nanotechnologyinventions. Surprisingly, the Undersecretaryblamed the excessive delays on nanotechnologycompanies, accusing them of poaching nan-otech-trained examiners en masse from the PTO[66]. I find the Undersecretary’s argument anexcuse for inefficiency and incompetence.

Furthermore, surprisingly broad patents innanomedicine continue to be issued by the PTO[18,19,21,22,53,67]. Obviously, this is partly theresult of court decisions in the past two decadesthat have made it easier to secure broad patents.During this period, laws have also tilted the tablein favor of patent holders, no matter how broador tenuous their claims. As a result, the PTOfaces an uphill task as it attempts to handle theenormous backlog of applications filed. It alsofaces a torrent of improperly granted patents,many of which are likely to be ‘re-examined’.

In this climate of patent proliferation, it isinevitable that, in the near future, there will bean increase in litigation. Most patent practition-ers regularly highlight one or more of the follow-ing problems while discussing nanomedicinepatents:

• An improper rejection of a patent applicationdue to an examiner’s erroneous conclusionthat the subject matter is not novel;

• Issuance of an ‘overly broad’ patent thatinfringes on previously issued patents andgives far too much control over a particularswath of basic technology, allowing the pat-entee to exclude competition unfairly. Thisresult runs the risk of impeding futuredownstream innovations;

• Issuance of a patent in spite of existing priorart that was overlooked or not uncovered bythe examiner during patent examination.

Naturally, any of the above results is unaccept-able. Issuance of patents of poor quality, or toomany invalid patents on early-stage research, islikely to cause enormous damage to commercial-ization efforts because it can result in one ormore of the following:

• Suppressing market growth and innovation;• Causing a loss of revenue, resources and time;• Discouraging industry from conducting R&D

and manufacturing;• Inducing unnecessary licensing;• Increasing the possibility of patent appeals

and infringement lawsuits;• Stifling high-quality inventions (introducing

noise into investment, valuation and contract-ing decisions) and undermining the patentsystem itself;

• Eroding public trust vis-à-vis nanomedicine;

One patent expert summarizes the impact ofpoor-quality patents in economic terms [68]:“Questionable patents can harm competitionand hinder innovation by forcing market par-ticipants to pay licensing royalties, incur sub-stantial legal expense to defend againstinfringement claims, engage in design-aroundefforts that raise costs and/or hinder productperformance … [A] patent holder can have realpower even without being a true inventorbecause the systems for patent issuance andpatent litigation are tilted in favor of patentapplicants and patent holders. The result is thatthe patent system, while intended to promoteinnovation, instead places sand in the gears ofour innovation engine.”

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Emerging nanomedicine patent thicketsCurrently, there are too many players holding toomany nanomedicine patents. This has createdthe current fragmented, messy patent landscape.Most experts agree that this patent landscape isalready producing ‘patent thickets’ that have thepotential of causing protracted legal battles. Thisis obviously an undesirable result and could eas-ily freeze nanomedicine development in itstracks. Patent thickets pose the biggest threat tocommercialization efforts in nanomedicine.

Patent thickets are defined broadly in academicdiscourse as ‘a dense web of overlapping IP rightsthat a company must hack its way through inorder to actually commercialize new technology’[69]. Such patent thickets, a result of multipleblocking patents, naturally discourage and stifleinnovation [69]. Claims in such patent thicketshave been characterized as broad, overlapping andconflicting. Therefore, business planners and pat-ent practitioners should steer company research-ers away from such potential patent thickets.They may also need to analyze the patent land-scape to gauge ‘white space’ opportunities (i.e., nooverlapping patents) prior to R&D efforts, patentfiling or commercialization activities (Figure 6).Classically, such an analysis into the number andquality of patents issued in a particular sector ofnanomedicine can highlight a particular technol-ogy trend, areas of high/low commercializationpotential and areas that indicate a high risk ofmarket entry.

According to a widely circulated market studypublished in 2005 [111], nanoscience researchersaround the world are steadily filing patents withthe hope of creating ‘toll booths’ that could slowdown future product development. Because therehas been an explosion of overlapping and broadpatent filing on nanomaterials, it is probable thatthe companies that want to use these buildingblocks in products will be forced to license patentsfrom many different players to implement theirinventions. The report focused on five funda-mental nanomaterials that are platforms fornumerous current and future nanomedicine appli-cations: carbon nanotubes, dendrimers, fullerenes,nanowires and quantum dots. The study identi-fied carbon nanotubes and quantum dots as ofparticular concern. The study noted that,although fullerenes and nanowires are relativelyfree of overlapping patent claims, the other catego-ries are attracting patent applications quickly. Forexample, the study found that a large number ofpatent claims for dendrimers have been assignedto recently acquired Dendritic NanoTechnologies,

Inc. (Mount Pleasant, MI, USA). It also notedthat quantum dot patent claims tend to cover thematerials themselves rather than specific applica-tions and that the patent situation for using car-bon nanotubes in electronics looks ‘messy’.Although some dominant or pioneering patentson carbon nanotubes will expire in the near future,a classic patent thicket seems to be developing inthe area of single-walled carbon nanotubes [13],where companies such as IBM (White Plains, NY,USA), NEC Corporation (Tokyo, Japan) and Car-bon Nanotechnologies, Inc. (Houston, TX, USA)are likely to stake out their claims aggressively.

To analyze the perceived patent thicket in anynanomedicine-related technology, a detailedlegal review of the claim set from the patents inthe thicket may be necessary before decisionsregarding patent filings or substantial investmenton commercialization are undertaken.

Upcoming nanomedicine patent battlesAt least in the US, patent grants in nanotech-nology and nanomedicine-related inventions arelikely to continue at a pace that is almost syn-chronous with funding. The aggressive mental-ity described above has not only producedoverlapping patents, but a race to patent any-thing ‘nano’ has resulted in a flood of exceed-ingly broad upstream nanopatents. Althoughbroad patents are generally awarded for pioneer-ing inventions, they should never be allowed ifprior art exists. Experts fear that nanomedicine’sconstantly growing patent estate may actuallyretard innovation because of uncertainty overwho is infringing on whose patent. The PTO isoften directly blamed for awarding numerouserroneous nanotechnology patents.

Clearly, this proliferation of unduly broad pat-ents and the resulting patent thickets will requirelitigation to sort out, especially if sectors ofnanomedicine become financially lucrative [67].At the present time, it seems that nanomedicinecompanies are avoiding costly court battles. Infact, there is hardly any nanomedicine (or nan-otechnology) patent litigation underway in theUSA. Companies sometimes avoid costly litiga-tion to prevent exposing their own patents, someof which may be based on a cursory review at thePTO whose validity may be questionable. In anycase, I believe that expensive litigation is as inev-itable as it was with the biotechnology industry,in which extensive patent litigation resulted onceproducts became commercially successful. Thereason for this is simple: at this stage, royaltiesmay be collected from potential infringers.

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When this comes about, in most patent battles,the larger entity with the deeper pockets will pre-vail, even if the brightest innovative stars are onthe other side. This situation is all too familiar tobusiness leaders. It leads to higher costs to con-sumers (if and when products are commercial-ized), while impeding the innovation processitself [60].

Ultimately, companies introducing new prod-ucts to the market will face considerable uncer-tainty regarding the validity of broad andpotentially overlapping patents held by others.The ongoing land grab will definitely worsen theproblem for companies striving to develop com-mercially viable products. In fact, nanomedicinestart-ups may soon find themselves in patent dis-putes with large, established companies, as wellas among themselves. Start-ups may also becomeattractive acquisitions for larger companiesbecause takeover is generally a cost-effectivealternative to litigation.

It is possible that companies may need toacquire costly licenses for patents from othercompanies in order to establish themselves. Itis also possible that companies may use theirpatents to exclude rather than license out. Fur-thermore, those who do license may do so at an

unreasonably high cost. However, I hope thatnone of these scenarios will come about.Instead, I hope that a more harmonious atmos-phere will prevail where cross-licensing agree-ments by start-ups and large corporations alikewill become the norm. In my view, liberal pat-ent licensing is another particularly effectivestrategy to maneuver through the patentthicket at this stage in the development ofnanomedicine, especially because the enforce-ability of so many patents is questionable. Itshould be noted, however, that when the totalnumber of owners of conflicting IP is relativelysmall, cross-licensing has been the answer. Butwhen the number of owners of conflicting IP isrelatively large, the transaction costs of cross-licensing may be too great for it to be effective.Also, critics consider cross-licensing as a settle-ment of a patent dispute that may not serve thepublic interest since cross-licensing (as com-pared with litigation) limits competition whenit is between competitors.

Navigating the nanopatent thicketFollowing are additional proposals that maycut through the nanomedicine patent gridlockand prevent widespread and wasteful litigation.

Figure 6. US patent landscape analysis according to nanomaterial platform.

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Formation of patent poolsThe multiple-party patent thicket problem maybe solved by the cooperative formation of ‘pat-ent pools’ by technologically competing entities.Patent pools are defined as legally permissiblecooperative agreements whereby the members ofthe pool have access to the patents of the entirepool in exchange for a set price. However, it isuncertain at this stage whether patent pools willbe a lawful, desirable or beneficial answer to thepatent thicket problem.

Government actions to encourage nonexclusive licensingSome patent practitioners have also suggestedthat the government must step in and use itsexisting authority under the Bayh–Dole Act toencourage non-exclusive licensing of founda-tional nanotechnology patents [62]. Under theBayh–Dole Act of 1980, universities and smallbusiness entities may retain patent ownershiprights if the research was funded by the US gov-ernment. The government retains a royalty-freelicense to any patented technology that is gen-erated as a result of such funding. Naturally,the Bayh–Dole Act will assist nanomedicine-related companies in the same way it helpedbiotechnology start-ups – by promoting thetransfer of university-owned patents funded bygovernment grants to the private sector, espe-cially since academia has become increasinglyaggressive in patenting its nanomedicine-related research.

Other government actionGovernment action, such as the imposition ofcompulsory licensing of upstream and/or foun-dational patents that have been financed bypublic funds, may assist in breaking up domi-nant patent monopolies [62]. Enforcement ofantitrust and unfair competition laws by thegovernment may encourage more cooperationbetween the various players and stimulate activecross-licensing and patent pooling.

There are, of course, other strategies availa-ble to prevent or navigate patent entangle-ments, both before and after a nanomedicinepatent issues [18,53]. Companies could alsofocus on trade secrets as a supplement to nano-medicine patents. Finally, a greater willingnesson the part of the patent applicant to providerelevant prior art, particularly nonpatent priorart, would be helpful to the patent examinerduring examination.

ConclusionSecuring valid and defensible patent protectionis critical to nanomedicine commercializationefforts. Although early forecasts for commercial-ization are promising, the emerging patentthicket in this arena of nanotech could be amajor stumbling block. Therefore, it is almostcertain that the enforceability of numerous USnanomedicine patents (similar to e-commercepatents previously) will be a major problem inthe future. Furthermore, due to the substantialannual increase in costs associated with main-taining and enforcing issued patents, enforcea-bility may be a problem when the patent holderlacks the resources to maintain the patent, orenforce the patent against potential infringers.

The PTO continues to be under enormousstrain and scrutiny. Reforms are urgentlyneeded to address issues ranging from poor pat-ent quality and questionable examination prac-tices to inadequate search capabilities, risingattrition and an enormous patent backlog.Numerous government and nongovernmententities have recently become more vocal intheir criticism of the PTO [70–73]. They haveproduced authoritative reports with detailedrecommendations regarding overhauling thePTO and the US patent system [70–73].

Reforms are urgently needed at the PTO inorder to restore the delicate balance betweeninnovation and competition. Without thesereforms, the cursory patent examination that iscurrently in place, coupled with patent prolifer-ation and patent pendency that is fast approach-ing one million, will result in the issuance of toomany invalid and unenforceable nanomedicinepatents. This will continue to generate acrowded, entangled patent landscape with fewopen-space opportunities for commercializa-tion. For many companies, navigating thisminefield will be an unattractive option.

Ownership of technology in the form of pat-ents is one thing, deriving sufficient economicvalue therefrom is another. Obtaining undeserv-ing patents and profiting by threatening litigation,rather than providing beneficial nanomedicineproducts, runs counter to the foundations of ourpatent system. Therefore, if the current dense pat-ent landscape becomes more entangled and thepatent thicket problem worsens, it will be themajor bottleneck to viable commercialization[74,75], negatively impacting the entire nanomedi-cine ‘revolution’. For investors, competing in thishigh-stakes patent game may prove too costly.

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Future perspective: the promise of nanomedicineThe potential future impact of nanomedicine onsociety could be huge. Nanomedicine could dras-tically improve a patient’s quality of life, reducesocietal and economic costs associated withhealthcare, offer early detection of pathologicalconditions, reduce the severity of therapy andresult in an improved clinical outcome for thepatient. Nanomedicine is, in a broad sense, theapplication of nanoscale technologies to the prac-tice of medicine, namely, for diagnosis, preven-tion and treatment of disease and to gain anincreased understanding of complex underlyingdisease mechanisms. The creation of nanodevicessuch as nanobots capable of performing real-timetherapeutic functions in vivo is one eventual long-term goal here. Advances in delivering nano-therapies, miniaturization of analytic tools,improved computational and memory capabili-ties and developments in remote communicationsare likely to be integrated. These efforts will crossnew frontiers to the understanding and practiceof medicine. The ultimate goal is obviously com-prehensive monitoring, repair and improvementof all human biologic systems – basically, anenhanced quality of life.

In fact, the nanopharma market is expected tosignificantly grow in the coming years. Analystsproject that by next year, the market for nano-biotechnology will exceed US$3 billion, reflect-ing an annual growth rate of 28% [76]. Accordingto another recent report, the US demand fornanotechnology-related medical products(nanomedicines, nanodiagnostics, nanodevicesand nanotech-based medical supplies) willincrease over 17% per year to US$53 billion in2011 and US$110 billion in 2016 [77]. Thisreport predicts that the greatest short-termimpact of nanomedicine will be in therapies anddiagnostics for cancer and CNS disorders.

I predict that in the coming years, significantresearch will be undertaken in the following areasof nanomedicine, generating both evolutionary aswell as revolutionary products [78]:

• Synthesis and use of novel nanomaterials andnanostructures (e.g., less antigenic);

• Biomimetic nanostructures (synthetic prod-ucts developed from an understanding of nat-ural or biological systems);

• Nanoanalytic tools, methods and instrumentsfor studying single or multisubunit biomole-cules or individual diseased cells (e.g., com-bining biochemical techniques with advanced

imaging and spectroscopy to provide insightsinto the behavior of single diseased cells andtheir surrounding micro-environment,leading to personalized therapy);

• Devices and nanosensors for early point-of-care detection of diseases and pathogens (e.g.,in vitro diagnostics such as molecular pathol-ogy or reading highly-integrated ultra-sensitive biochips via devices that rely uponthe polymerase chain reaction coupled withmicro/nano fluidics);

• Identification and quantification of novel ordisease-related biologic biomarkers/tar-gets/receptors/ligands for imaging, diagnosisand therapy (e.g., for advising patients of theincreased risks of certain cancers, neuro-degenerative diseases and cardiovascular dis-eases, thereby providing an avenue forpersonalized prevention regimens);

• Construction of smart multifunctional biologicnanostructures, devices, implants and systemsthat combine/integrate diagnosis, targeted site-specific drug delivery and imaging (combinedimaging and biochemical assays will allow trac-ing the drug path, following therapy progressafter activation at a specific site as well as fol-low-up monitoring of the tissue site/patientafter the acute therapy is completed);

• Nanotechnology for tissue engineering (nano-structured scaffolds) and regenerative medicine;

• Nano-imaging or molecular imaging via fabri-cation of noninvasive in vivo analytic nanotoolswith improved sensitivity and resolution formolecular imaging and for studying pathologicprocesses in vivo (main benefits include earlydetection of disease as well as monitoring ofvarious disease stages);

• Nanodevices that will be able to cross biologi-cal barriers (e.g., to deliver active agents to thebrain cancer cells by crossing the generallyimpenetrable blood–brain barrier);

• Miniaturizing of devices for reduced inva-siveness, coupled with surface modificationor ‘fictionalization’ to render the device more‘biologic’, offers enhanced accuracy andtherapeutic potential;

• In vivo nanosensors incorporated into stimuli-sensitive devices (e.g., in catheters) could providedata on physiological status and identify pathol-ogy/defects that could enhance patient outcome.

Drug delivery is one sector of nanomedicinewhere development is progressing more rapidly[41,45–49,76]. In fact, this arena of nanomedicine isalready producing significant results. I list below

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Executive summary

• Big pharma’s businessexpiration on several bdictating that new R&pipeline with novel conanotechnology and

• Securing valid and denanomedicine comme

• The US National Nanonanomedicine perspeUS Patent and Tradem

• The burgeoning numbsurprisingly broad pateenforceability of nume

• The PTO continues topatent quality and qusoaring patent backlo

• Many critical patent isformation of patent pBayh-Dole Act of 198

• A robust patent systestimulate market growlawsuits.

• Nanomedicine is hereare a few innovative nMany more potential

some examples of innovative products that Ienvision in the drug-delivery arena that cleverlyintegrate biological, information and materialsciences. Some of these products could be availa-ble in the next 5–7 years, while others lie on thedistant horizon. Nanotech-based drug deliverymay involve:

• Miniaturized nanofluidic devices and systemsthat more efficiently transport fluids to thesite of delivery, preventing turbulence andmixing (because fluids move with laminarflow through micro/nanochannels);

• More efficient site-specific or precision target-ing via nanomedicines (functionalized nano-particles or nanoencapusulated/nanocoateddrugs) with reduced systemic side effects andbetter patient compliance;

• Close-looped drug-delivery nanodevices andimplants (also known as ‘smart pills’) contain-ing sensors (to monitor biomolecules) anddrug reservoirs (for precise delivery) locatedon the same chip;

• Microsurgical devices, molecular motors ornanobots (could be manmade or be engineeredmicrobes) that are capable of navigatingthroughout the body to carry out targeted heal-ing, such as repairing damaged tissues, destroy-ing tumors or viruses and even performing genetherapy or vaccination.

Funding & disclosureThere is no conflict of interest reported by the author of thismanuscript. This report reflects the current views of the author,which are likely to evolve. Furthermore, they should not beattributed, in whole or in part, to the organizations with whichhe is affiliated, nor should they be considered as expressing anopinion with regard to the merits of any particular company orproduct discussed herein. Nothing contained herein is to be con-sidered as the rendering of legal advice. This paper primarilyfocuses on US patents and the US patent system.

The author thanks Michael Berger of Nanowerk LLC(Honolulu, Hawaii, USA) for kindly providing Figure 1B.The author thanks Lux Research, Inc. (New York, NY,USA) and Foley & Lardner (Washington, DC, USA) forkindly providing the remaining figures.

model, which relies on a few blockbusters to generate enormous profits, is clearly broken. Patent lockbusters in recent years is already altering the drug landscape. Additionally, numerous market forces are D approaches be developed and implemented so that drug companies can continue to discover and fill the mpounds (or develop reformulations of older compounds). Some of these strategies revolve around

miniaturization. In fact, nanomedicine is already having an enormous impact in this regard.

fensible patent protection is critical to the nanomedicine ‘revolution’. Although early forecasts for rcialization are encouraging, there are bottlenecks, including emerging thickets of patent claims.

technology Initiative’s widely-cited definition of nanotechnology is irrelevant and confusing from a ctive. It is also the cause of the inadequate patent classification system that was recently developed by the ark Office (PTO).

er of new nanomedicine patent applications filed at the PTO, coupled with the continued issuance of nts, is creating a chaotic, tangled patent landscape where competing players are unsure as to the validity and rous issued patents. If this trend continues, it could stifle competition and limit access to some inventions.

be under enormous strain and scrutiny. Reforms are urgently needed to address issues ranging from poor estionable examination practices to inadequate search capabilities, rising patent examiner attrition and a g.

sues and scenarios will take center stage in the near future and impact nanomedicine commercialization: ools, cross-licensing activity, patent litigation, Congress’s effort at reforming the US patent system, the 0 and the Supreme Court’s increased scrutiny and interest in patent law.

m will aid nanomedicine companies that are striving to develop commercially viable products. Valid patents th and innovation, generate revenue, prevent unnecessary licensing and greatly reduce infringement

to stay and will generate both evolutionary as well as revolutionary products in the future. Currently, there anomedicine products on the market that cleverly integrate biological, information and material sciences. applications are under consideration.

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