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− | <h1> Patenting a New Form of Taxol Fermentation </h1>
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− | <h2> Abstract </h2>
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− | <p> Taxol, also known as pacilitaxel, is a widely used chemotherapy drug typically
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− | extracted from the Yew tree. Mere extraction, however, does not yield sustainable returns
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− | because too-frequent extraction involves destroying the Yew tree source. Demand for Taxol
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− | has outstripped supply, and scientists have turned to developing Taxol in plant cells followed
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− | by industrial fermentation. The Duke University International Genetically Engineered
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− | Machine Project looks to go a step further, by generating Taxol in bacteria cell cultures
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− | instead of plant cell cultures. In order to use this invention to boost the market supply of
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− | Taxol, the IGEM team will eventually need a corporate or non-profit partner, and this partner
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− | will only be incentivized to participate if the IGEM team can offer exclusive licensing. Thus, the
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− | success of IGEM’s new genetically engineered bacteria largely hinges on its patentability with
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− | the United States Patent and Trademark Office. This report walks through the relevant patent
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− | requirements, analyzes the case law, and comes to the conclusion that IGEM’s new genetically
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− | engineered bacteria meets the conditions for successful patentability. </p>
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− |
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− | <br>
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− | <h2> Introduction </h2>
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− | <p> Prior research has already shown Taxol to be an effective chemical in combatting
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− | cancer. As explained by a professor at the University of Massachusetts-Amherst, the
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− | compound “binds to micro-tubules, which are important in cell division, and prevents the
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− | cancer cells from dividing properly.” <br> <br>
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− | However, just because a product is useful does not mean supply has kept pace with
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− | rising demand. Taxol is primarily obtained by extracting it from Yew trees, which naturally
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− | synthesize the product. Given the solvents and treatment necessary to do so, however, this
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− | approach also destroys the very same Yew trees in the process. As such, extraction is
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− | unlikely to achieve demand-supply equilibrium in the market. Researchers have since
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− | pivoted to modifying plant cell cultures to produce Taxol and other significant precursors
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− | found along the metabolic pathway. These plant cell cultures are in turn used in industrial
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− | processes designed to produce Taxol on a substantial scale. Even this, however, is not the
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− | most efficient solution to the current shortage—the plant cell’s complex infrastructure and
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− | subsequent energy needs have prevented the cell’s resources from being fully directed
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− | towards Taxol production. Low product yield is typically the result. <br><br>
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− | The 2016 Duke University International Genetically Engineered Machine team’s goal
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− | is to produce Taxol more efficiently, by using bacteria cell cultures rather than plant cells.
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− | The process of optimizing bacteria to produce a product for later industrial fermentation
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− | has already been demonstrated, but its application to Taxol has not. The IGEM team has
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− | worked on characterizing five enzymes involved in the natural process of Taxol production,
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− | and then merging them into one strain by genetically engineering the DNA of the bacteria
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− | culture. At the end of this process, the bacteria culture produces Taxol, with less energy
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− | expenditure than was required in plant cells and subsequently higher yield. <br><br>
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− | But a more efficient process is meaningless if the means to boost market supply are
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− | not available, which requires cooperation with a biopharmaceutical company. The Duke
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− | IGEM project does not on its own have the resources to mass produce Taxol through
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− | industrial fermentation, so licensing the new bacteria cell culture to a pharmaceutical
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− | manufacturer is the logical next step. <br> <br><br>
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− |
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− |
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− | <div class="column full-size">
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− | “A company that owns rights in a patent, know-how, or other IP asset, but cannot or
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− | does not want to be involved in the manufacturing of products, could benefit from
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− | licensing out of such IP assets by relying on the better manufacturing capacity,
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− | wider distribution outlets, greater local knowledge and management expertise of
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− | another company (the licensee)” <br> <br><br>
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− | </div>
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− |
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− |
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− | Details of such a licensing agreement would need to be worked out in individual contract
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− | negotiations. For example, the manufacturer might require more research by IGEM at the
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− | front-end before agreeing to commercialize the product5. Before any negotiation can take
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− | place, however, the manufacturer needs reassurance the venture will be profitable. These
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− | industries are not in the business of charity. Acquiring a patent on the new genetically
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− | engineered bacteria will provide the necessary financial incentive. <br><br>
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− | The remainder of this report will outline the fundamentals of patent law and
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− | requirements to getting a patent approved by the United States Patent and Trademark
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− | Office. It will explain out the main roadblocks towards getting approved, but will ultimately
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− | provide a case for a successful patent prosecution. </p><br><br><br>
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− |
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− | <h2>Fundamentals of Patent Law </h2>
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− | <p> Patent protection gives the right-holder what is known as a “negative right” to
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− | prohibit others from making, using, selling, offering to sell, or importing from elsewhere
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− | the patented invention. Because the grant of a patent removes the application of new
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− | knowledge from the public domain for 20 years from the date of filing, the criteria for
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− | patentability are strict. There are four key patent criteria—novelty, utility, nonobviousness,
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− | and disclosure. <br><br>
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− | Each of the four criteria is equally important, but some are harder to prove than
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− | others. Disclosure is the simplest. It requires that when filing for the patent, the rightseeker
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− | disclose an explanation of the product in the “best mode” possible, such that another
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− | person “reasonably skilled” in the field would be able to recreate the product. While the
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− | simplest to fulfill, disclosure is typically the most frightening for the right-seeker, because
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− | the law asks that the invention be explained to the public before the patent right has
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− | officially been granted. Careful discussion with the potential licensee and lawyers will be
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− | crucial in this stage to minimize risk. Next, the utility requirement asks that the potential
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− | usefulness of the product be proven. With the IGEM team’s documentation of the enhanced
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− | efficiency of Taxol production, the utility requirement will not pose a significant obstacle. <br><br>
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− | Novelty and non-obviousness are the strictest, and hardest to meet, criteria for
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− | patentability. The novelty requirement essentially asks whether the invention is “new”
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− | compared to prior inventions in the field that existed more than a year prior to the date of
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− | filing the patent application. The America Invents Act of 2011 sets out specific tests for
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− | novelty: <br><br>
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− | <ul>
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− | <li> The product cannot have been patented before. </li>
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− | <li> The product cannot have been described in a printed publication more
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− | than a year prior to the date of filing the application. </li>
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− | <li> The product cannot be in the public domain more than a year prior to
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− | the date of filing the application. </li>
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− | <li> The product cannot have been sold more than a year prior to the date
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− | of filing the application. </li>
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− | </ul> <br>
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− | Lastly, the nonobviousness criteria asks whether “an ordinary person with skill” in the
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− | designated field could have come up with the same invention by virtue of his expertise, or
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− | whether the invention needed a “creative leap.” <br> <br>
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− | The specific application of the utility, novelty and nonobviousness requirements will
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− | be explained in the “analysis” portion of this report. Before diving into that territory,
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− | however, a brief history of Taxol’s relationship to intellectual property law is instructive. </p>
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− |
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− | <h2> Taxol, Historically</h2>
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− | <p> For several years, the pharmaceutical giant Bristol-Myers Squibb had exclusive
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− | rights to market Taxol. Taxol was first discovered in 1962, after researchers from the
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− | United States Department of Agriculture and the National Cancer Institute extracted the
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− | compound from the Taxus brevifolia Yew tree. The initial extract was not pure Taxol, but
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− | within two years researchers at Research Triangle Park isolated the Taxol in pure form. In 1977, the National Cancer Institute granted a professor at Yeshiva University a grant to
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− | study the compound’s functions, and Dr. Susan Horwitz eventually discovered its potential
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− | in preventing the division of cancer cells. The NCI ran clinical trials to prove the
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− | compound’s efficacy, and upon doing so began looking to get a pharmaceutical company
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− | involved. In 1991, a “cooperative research and development agreement” was awarded to
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− | Bristol-Myers Squibb, along with an exclusive right to market the drug for five years. <br> <br>
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− | The exclusive right to market the drug was legally problematic for several reasons.
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− | First and foremost, it superseded patent law. As mentioned before, patent law provides the
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− | patent holder “negative rights” to prevent others from using the invention. But a core
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− | principle of patent law is that “the laws of nature, physical phenomena, and abstract ideas”
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− | cannot be patented. The Plant Patent Act of 1930 also gives inventors the ability to patent
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− | plants, but only to the extent they are “new varieties of many asexually produced plants.”
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− | In essence, the principles mentioned above and the Plant Patent Act reinforce a more
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− | general idea—that inventions are patentable, discoveries are not. Extracting a naturally
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− | occurring Taxol compound from a tree is a discovery, not an invention, and simply isolating
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− | the compound does not change that it already existed in nature. In 2013, the Supreme
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− | Court more concretely noted a “natural product” exception to patentable subject matter, and that mere isolation does not constitute a “marked difference” allowing for
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− | patentability. In essence, the NCI granted Bristol-Myers Squibb an exclusive right to
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− | something that was not eligible for a patent in the first place. <br> <br>
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− | The initial NCI agreement with Bristol-Myers Squibb included a fair pricing
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− | agreement, but monopoly prices indicate the company got around such requirements.
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− | When it entered the market, a single dose was $1,800 and full treatment was between
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− | $10,000 and $20,00019. In 2002, a lawsuit alleged that Bristol-Myers Squibb was extending
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− | its monopoly by misusing and acquiring patents in ways it was not entitled to (by failing to
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− | inform the PTO about prior Taxol research in the public domain) in conjunction with
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− | another company American BioScience. The two companies allegedly did this, the
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− | complaint alleged, to prevent generic competitors from entering the market and
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− | dramatically weakening their market share. A related Federal Trade Commission
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− | complaint explains the alleged patent fraud in considerable detail: <br> <br> <br>
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− | “Among other things, BMS: paid a would-be generic competitor millions of dollars to
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− | abandon its patent challenge and agree to withhold competition until patent expiry;
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− | misled the United States Food and Drug Administration about the scope, validity,
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− | and enforceability of its patents and abused FDA regulations to block generic entry;
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− | breached its duty of candor and food faith before the Patent and Trademark Office.” <br> <br> <br>
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− | Eventually, an FTC proposed order barred Bristol-Myers Squibb from “seeking to enforce,
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− | or collect royalties on, any Taxol patent if the infringement claim involves the use of
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− | Taxol.” Bristol eventually backed off, perhaps due to the FTC pressure. At the end of the
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− | legal disputes, generic Taxol became accessible on the market and several companies have
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− | entered that market, including IVAX Pharmaceuticals. <br> <br>
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− | The core lessons to be taken away from this protracted legal dispute are that Taxol
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− | is not patent-protected, and generic Taxol is available on the market. However, methods of
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− | producing Taxol are still patent-eligible. The IGEM team should still look to file the
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− | genetically modified bacteria with the patent office, in the hopes of later licensing to a
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− | pharmaceutical company. </p>
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− |
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− | <h2> Patentability of the IGEM Product </h2>
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− | <p>This section of the report will walk through each of the three (excluding disclosure,
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− | which is done with a lawyer’s expertise at the time of the filing) requirements for
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− | patentability. <br> <br>
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− | Meeting the utility requirement will not be hard for the IGEM team. The most
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− | applicable case in terms of utility for the process of generating a chemical compound is
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− | Brenner v. Manson, decided by the Supreme Court in 1966. Andrew Manson had filed a
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− | patent for a process to develop a steroid, but was unable to specifically prove what the value of the steroid would actually be. Manson argued instead, that there is utility solely in
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− | creating the compound regardless of the compound’s utility, and that the steroid was
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− | related to other compounds that had demonstrable utility. In order to ensure that a “patent
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− | is not a hunting license,” the Supreme Court rejected both claims. It held that “specific
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− | utility”—of the compound and of the process—is necessary for patentability. The
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− | effectiveness of Taxol has already been proven in theory and practice, so what the IGEM
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− | team has to show is that creating a single enzyme stream within bacterial DNA is actually a
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− | more efficient production process than other methods. This should not pose a substantial
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− | obstacle.
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− | Before addressing novelty and nonobviousness, there is some important case law on
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− | the fundamental patentability of bacteria that must be considered. In Funk Bros. Seed
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− | Corporation v. Kalo Inoculant Corporation in 1948, the Supreme Court held that merely
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− | aggregating several types of bacteria into one culture is “hardly more than packaging of the
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− | inoculants” and not patentable because it is essentially a natural phenomenon: <br> <br> <br>
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− | “The combination of species produces no new bacteria, no change in the six species
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− | of bacteria, and no enlargement of the range of their utility. Each species has the
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− | same effect it always had. The bacteria perform in their natural way.” <br> <br> <br>
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− | Reading into this case, there are some requirements laid out for generating patentable
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− | bacteria:
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− | <ul> <li>The bacteria must be new OR </li> <li>The bacteria species must be changed OR </li>
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− | <li> The range of utility must be enlarged </li>
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− | </ul> <br>
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− | The bacteria produced by the IGEM team will likely pass this test, because it is being
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− | genetically modified to produce a strain of five enzymes the bacteria did not naturally
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− | produce before. The Supreme Court’s decision in Diamond v. Chakrabarty confirms this
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− | intuition. In Diamond, the patent-seeker had genetically modified bacteria to break down
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− | crude oil, by incorporating multiple plasmids—each of which broke down a component of
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− | crude oil—into one bacterium. The Supreme Court decided the new bacteria were
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− | patentable, because it was a “non-naturally occurring manufacture or composition of
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− | matter.” Instead of deciding that animate objects are simply non-patentable, the Supreme
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− | Court decided that animate objects are patentable as long as that they perform functions
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− | that they could not have done in nature absent human intervention. Incorporating five
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− | enzymes into the DNA of a new bacterium—allowing it to generate Taxol, something the
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− | bacterium had not done before—falls in line with Diamond’s holding27. IGEM’s genetically
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− | engineered bacteria are fundamentally patentable, pending decisions on novelty and
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− | nonobviousness. <br> <br>
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− | Novelty is a tougher rung, but one that can still be met by genetically engineered
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− | bacteria. As mentioned before, there are four ways novelty can be precluded as specified by
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− | the America Invents Act:
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− |
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− | <ul> <li>The product cannot have been patented before. </li>
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− | <li>The product cannot have been described in a printed publication more
| |
− | than a year prior to the date of filing the application. </li> <li>The product cannot be in the public domain more than a year prior to
| |
− | the date of filing the application. </li> <li>The product cannot have been sold more than a year prior to the date
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− | of filing the application.</li>
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− | </ul>
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− | <br>
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− | The last requirement will not be a consideration here, as the product IGEM would claim in
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− | the patent is the genetically modified bacterium, not Taxol itself. <br><br> <br>
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− | With regards to the printed publication and public domain requirements, there is an
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− | immediate irony that needs to be addressed. In In re Hall—considered by the United States
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− | Court of Appeals For The Federal Circuit in 1986—the court held that a doctoral thesis
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− | published in a library more than a year prior to filing, even when filed by the patent-seeker,
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− | was a violation of the novelty requirement. In other words, if the IGEM team were to
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− | publish the contents of the genetically modified bacteria more than a year prior to filing a
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− | patent, patentability might be barred. There is a statutory exception, however, indicating
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− | that you will not be barred if you file within one year of making the printed publication or
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− | otherwise disclosing it publically. Once IGEM presents its work, the clock is ticking. <br> <br>
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− | A cursory search of the Patent and Trademark Office database did not find anything
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− | that would bar IGEM’s invention, in terms of prior patents. An internet search also did not
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− | yield evidence that the bacteria engineered by IGEM is already in the public domain. <br> <br>
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− | Non-obviousness is the hardest requirement for the IGEM team to fulfill. This
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− | requirement asks whether or not another person with reasonable skill in the field could
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− | have generated the bacteria, or if it required a “creative leap” on the part of the inventors. Several factors weigh against a successful finding of nonobviousness. First, the process of
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− | genetically modifying bacteria to create new products is old science. Secondly, there are
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− | other labs in the country also working to use bacteria in producing Taxol. In 2010, for
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− | example, “U.S. and Singaporean researchers engineered strains of E. Coli that produce two
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− | precursors of the cancer drug Taxol.30” The Massachusetts Institute of Technology was also
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− | doing something similar in 201031. This does not make it impossible for IGEM to fulfill the
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− | nonobviousness requirement—especially because the cited examples involve precursors,
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− | whereas IGEM is using the bacteria to produce Taxol itself. The team’s lawyers would need
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− | to argue to the PTO that the unique choice of enzymes to include in the bacteria to produce
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− | the final Taxol product was a “creative leap,” not obtained by other researchers despite
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− | tinkering with similar technology. <br> <br>
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− | Ultimately, the utility, novelty and nonobviousness requirements can all be met with
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− | regards to the specific genetically modified bacteria. The process of making that bacteria
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− | would likely not be patentable due to nonobviousness requirement, but the bacterium itself
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− | could be. The exclusive right to produce a bacterium that makes Taxol production more
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− | efficient could be of immense value to a pharmaceutical licensee. </p>
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− |
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− | <h2> Next Steps </h2>
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− | <p> Through correspondence with Eric Wagner, an attorney in Duke University’s Office
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− | of Licensing and Ventures, it is clear that the group itself does not have the rights to the
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− | product. Rather, because Levine Science Research Laboratory facilities were used in
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− | conjunction with a faculty mentor, Duke University owns anything created from the work.
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− | Any filing for patentability and subsequent licensing would have to be done in conjunction
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− | with Duke University, which could be a benefit given the University’s institutional
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− | resources. If IGEM plans on patenting this bacteria, the next step should be meeting with
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− | the Office of Licensing and Ventures, informing them of the product and negotiating with
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− | them what licenses and royalties should ensue. </p>
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− |
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− | <h2> Conclusion </h2>
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− | <p> The Duke University IGEM team has created a new genetically modified bacteria
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− | that produces Taxol more efficiently than past fermentation efforts using plant cells. In
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− | order to expand the market supply of Taxol, licensing this bacteria to a pharmaceutical
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− | company is almost essential, as is acquiring the patent to do so. Specifically, the mostlogical
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− | patent would be on the genetically modified bacteria itself, which provides a
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− | stronger case for meeting the patent requirements than other possibilities such as the
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− | process or Taxol. <br> <br>
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− | IGEM has to work with the University to license out the product to either a
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− | pharmaceutical company or a non-profit. There is a trade-off: the former would be able to
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− | fund more production in bulk, but the latter would likely have a more distributive interest
| |
− | (and less prone to price-gouging). Either way, the patent is the surest way to guarantee
| |
− | active interest by another party. <br> <br>
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− | Should the patent be denied, the invention still has value. The best course of action in
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− | that instance would be academic publication and dissemination of the work to various nonprofits
| |
− | and academic circles. Without patent rights, the group would be hard-pressed to
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− | receive further funding, but by expanding the store of knowledge other pharmaceutical
| |
− | professionals could work to supplement IGEM’s work. Eventually, this could lead to an increase in Taxol supply, just divorced from the initial IGEM work compared to if a patent
| |
− | was acquired. </p>
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− |
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− | <h2> References <h2>
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− | <p> STILL TO DO!!!!! </p>
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