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<h1> Patenting a New Form of Taxol Fermentation </h1>
 
<h2> Abstract </h2>
 
<p> Taxol, also known as pacilitaxel, is a widely used chemotherapy drug typically
 
extracted from the Yew tree. Mere extraction, however, does not yield sustainable returns
 
because too-frequent extraction involves destroying the Yew tree source. Demand for Taxol
 
has outstripped supply, and scientists have turned to developing Taxol in plant cells followed
 
by industrial fermentation. The Duke University International Genetically Engineered
 
Machine Project looks to go a step further, by generating Taxol in bacteria cell cultures
 
instead of plant cell cultures. In order to use this invention to boost the market supply of
 
Taxol, the IGEM team will eventually need a corporate or non-profit partner, and this partner
 
will only be incentivized to participate if the IGEM team can offer exclusive licensing. Thus, the
 
success of IGEM’s new genetically engineered bacteria largely hinges on its patentability with
 
the United States Patent and Trademark Office. This report walks through the relevant patent
 
requirements, analyzes the case law, and comes to the conclusion that IGEM’s new genetically
 
engineered bacteria meets the conditions for successful patentability. </p>
 
 
<br>
 
<h2> Introduction </h2>
 
<p> Prior research has already shown Taxol to be an effective chemical in combatting
 
cancer. As explained by a professor at the University of Massachusetts-Amherst, the
 
compound “binds to micro-tubules, which are important in cell division, and prevents the
 
cancer cells from dividing properly.” <br> <br>
 
However, just because a product is useful does not mean supply has kept pace with
 
rising demand. Taxol is primarily obtained by extracting it from Yew trees, which naturally
 
synthesize the product. Given the solvents and treatment necessary to do so, however, this
 
approach also destroys the very same Yew trees in the process. As such, extraction is
 
unlikely to achieve demand-supply equilibrium in the market. Researchers have since
 
pivoted to modifying plant cell cultures to produce Taxol and other significant precursors
 
found along the metabolic pathway. These plant cell cultures are in turn used in industrial
 
processes designed to produce Taxol on a substantial scale. Even this, however, is not the
 
most efficient solution to the current shortage—the plant cell’s complex infrastructure and
 
subsequent energy needs have prevented the cell’s resources from being fully directed
 
towards Taxol production. Low product yield is typically the result. <br><br>
 
The 2016 Duke University International Genetically Engineered Machine team’s goal
 
is to produce Taxol more efficiently, by using bacteria cell cultures rather than plant cells.
 
The process of optimizing bacteria to produce a product for later industrial fermentation
 
has already been demonstrated, but its application to Taxol has not. The IGEM team has
 
worked on characterizing five enzymes involved in the natural process of Taxol production,
 
and then merging them into one strain by genetically engineering the DNA of the bacteria
 
culture. At the end of this process, the bacteria culture produces Taxol, with less energy
 
expenditure than was required in plant cells and subsequently higher yield. <br><br>
 
But a more efficient process is meaningless if the means to boost market supply are
 
not available, which requires cooperation with a biopharmaceutical company. The Duke
 
IGEM project does not on its own have the resources to mass produce Taxol through
 
industrial fermentation, so licensing the new bacteria cell culture to a pharmaceutical
 
manufacturer is the logical next step. <br> <br><br>
 
 
 
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“A company that owns rights in a patent, know-how, or other IP asset, but cannot or
 
does not want to be involved in the manufacturing of products, could benefit from
 
licensing out of such IP assets by relying on the better manufacturing capacity,
 
wider distribution outlets, greater local knowledge and management expertise of
 
another company (the licensee)” <br> <br><br>
 
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Details of such a licensing agreement would need to be worked out in individual contract
 
negotiations. For example, the manufacturer might require more research by IGEM at the
 
front-end before agreeing to commercialize the product5. Before any negotiation can take
 
place, however, the manufacturer needs reassurance the venture will be profitable. These
 
industries are not in the business of charity. Acquiring a patent on the new genetically
 
engineered bacteria will provide the necessary financial incentive. <br><br>
 
The remainder of this report will outline the fundamentals of patent law and
 
requirements to getting a patent approved by the United States Patent and Trademark
 
Office. It will explain out the main roadblocks towards getting approved, but will ultimately
 
provide a case for a successful patent prosecution. </p><br><br><br>
 
 
<h2>Fundamentals of Patent Law </h2>
 
<p> Patent protection gives the right-holder what is known as a “negative right” to
 
prohibit others from making, using, selling, offering to sell, or importing from elsewhere
 
the patented invention. Because the grant of a patent removes the application of new
 
knowledge from the public domain for 20 years from the date of filing, the criteria for
 
patentability are strict. There are four key patent criteria—novelty, utility, nonobviousness,
 
and disclosure. <br><br>
 
Each of the four criteria is equally important, but some are harder to prove than
 
others. Disclosure is the simplest. It requires that when filing for the patent, the rightseeker
 
disclose an explanation of the product in the “best mode” possible, such that another
 
person “reasonably skilled” in the field would be able to recreate the product. While the
 
simplest to fulfill, disclosure is typically the most frightening for the right-seeker, because
 
the law asks that the invention be explained to the public before the patent right has
 
officially been granted. Careful discussion with the potential licensee and lawyers will be
 
crucial in this stage to minimize risk. Next, the utility requirement asks that the potential
 
usefulness of the product be proven. With the IGEM team’s documentation of the enhanced
 
efficiency of Taxol production, the utility requirement will not pose a significant obstacle. <br><br>
 
Novelty and non-obviousness are the strictest, and hardest to meet, criteria for
 
patentability. The novelty requirement essentially asks whether the invention is “new”
 
compared to prior inventions in the field that existed more than a year prior to the date of
 
filing the patent application. The America Invents Act of 2011 sets out specific tests for
 
novelty: <br><br>
 
<ul>
 
<li> The product cannot have been patented before. </li>
 
<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
 
of filing the application. </li>
 
</ul> <br>
 
Lastly, the nonobviousness criteria asks whether “an ordinary person with skill” in the
 
designated field could have come up with the same invention by virtue of his expertise, or
 
whether the invention needed a “creative leap.” <br> <br>
 
The specific application of the utility, novelty and nonobviousness requirements will
 
be explained in the “analysis” portion of this report. Before diving into that territory,
 
however, a brief history of Taxol’s relationship to intellectual property law is instructive. </p>
 
 
<h2> Taxol, Historically</h2>
 
<p> For several years, the pharmaceutical giant Bristol-Myers Squibb had exclusive
 
rights to market Taxol. Taxol was first discovered in 1962, after researchers from the
 
United States Department of Agriculture and the National Cancer Institute extracted the
 
compound from the Taxus brevifolia Yew tree. The initial extract was not pure Taxol, but
 
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
 
study the compound’s functions, and Dr. Susan Horwitz eventually discovered its potential
 
in preventing the division of cancer cells. The NCI ran clinical trials to prove the
 
compound’s efficacy, and upon doing so began looking to get a pharmaceutical company
 
involved. In 1991, a “cooperative research and development agreement” was awarded to
 
Bristol-Myers Squibb, along with an exclusive right to market the drug for five years. <br> <br>
 
The exclusive right to market the drug was legally problematic for several reasons.
 
First and foremost, it superseded patent law. As mentioned before, patent law provides the
 
patent holder “negative rights” to prevent others from using the invention. But a core
 
principle of patent law is that “the laws of nature, physical phenomena, and abstract ideas”
 
cannot be patented. The Plant Patent Act of 1930 also gives inventors the ability to patent
 
plants, but only to the extent they are “new varieties of many asexually produced plants.”
 
In essence, the principles mentioned above and the Plant Patent Act reinforce a more
 
general idea—that inventions are patentable, discoveries are not. Extracting a naturally
 
occurring Taxol compound from a tree is a discovery, not an invention, and simply isolating
 
the compound does not change that it already existed in nature. In 2013, the Supreme
 
Court more concretely noted a “natural product” exception to patentable subject matter, and that mere isolation does not constitute a “marked difference” allowing for
 
patentability. In essence, the NCI granted Bristol-Myers Squibb an exclusive right to
 
something that was not eligible for a patent in the first place. <br> <br>
 
The initial NCI agreement with Bristol-Myers Squibb included a fair pricing
 
agreement, but monopoly prices indicate the company got around such requirements.
 
When it entered the market, a single dose was $1,800 and full treatment was between
 
$10,000 and $20,00019. In 2002, a lawsuit alleged that Bristol-Myers Squibb was extending
 
its monopoly by misusing and acquiring patents in ways it was not entitled to (by failing to
 
inform the PTO about prior Taxol research in the public domain) in conjunction with
 
another company American BioScience. The two companies allegedly did this, the
 
complaint alleged, to prevent generic competitors from entering the market and
 
dramatically weakening their market share. A related Federal Trade Commission
 
complaint explains the alleged patent fraud in considerable detail: <br> <br> <br>
 
“Among other things, BMS: paid a would-be generic competitor millions of dollars to
 
abandon its patent challenge and agree to withhold competition until patent expiry;
 
misled the United States Food and Drug Administration about the scope, validity,
 
and enforceability of its patents and abused FDA regulations to block generic entry;
 
breached its duty of candor and food faith before the Patent and Trademark Office.” <br> <br> <br>
 
Eventually, an FTC proposed order barred Bristol-Myers Squibb from “seeking to enforce,
 
or collect royalties on, any Taxol patent if the infringement claim involves the use of
 
Taxol.” Bristol eventually backed off, perhaps due to the FTC pressure. At the end of the
 
legal disputes, generic Taxol became accessible on the market and several companies have
 
entered that market, including IVAX Pharmaceuticals. <br> <br>
 
The core lessons to be taken away from this protracted legal dispute are that Taxol
 
is not patent-protected, and generic Taxol is available on the market. However, methods of
 
producing Taxol are still patent-eligible. The IGEM team should still look to file the
 
genetically modified bacteria with the patent office, in the hopes of later licensing to a
 
pharmaceutical company. </p>
 
 
<h2> Patentability of the IGEM Product </h2>
 
<p>This section of the report will walk through each of the three (excluding disclosure,
 
which is done with a lawyer’s expertise at the time of the filing) requirements for
 
patentability. <br> <br>
 
Meeting the utility requirement will not be hard for the IGEM team. The most
 
applicable case in terms of utility for the process of generating a chemical compound is
 
Brenner v. Manson, decided by the Supreme Court in 1966. Andrew Manson had filed a
 
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
 
creating the compound regardless of the compound’s utility, and that the steroid was
 
related to other compounds that had demonstrable utility. In order to ensure that a “patent
 
is not a hunting license,” the Supreme Court rejected both claims. It held that “specific
 
utility”—of the compound and of the process—is necessary for patentability. The
 
effectiveness of Taxol has already been proven in theory and practice, so what the IGEM
 
team has to show is that creating a single enzyme stream within bacterial DNA is actually a
 
more efficient production process than other methods. This should not pose a substantial
 
obstacle.
 
Before addressing novelty and nonobviousness, there is some important case law on
 
the fundamental patentability of bacteria that must be considered. In Funk Bros. Seed
 
Corporation v. Kalo Inoculant Corporation in 1948, the Supreme Court held that merely
 
aggregating several types of bacteria into one culture is “hardly more than packaging of the
 
inoculants” and not patentable because it is essentially a natural phenomenon: <br> <br> <br>
 
“The combination of species produces no new bacteria, no change in the six species
 
of bacteria, and no enlargement of the range of their utility. Each species has the
 
same effect it always had. The bacteria perform in their natural way.” <br> <br> <br>
 
Reading into this case, there are some requirements laid out for generating patentable
 
bacteria:
 
<ul> <li>The bacteria must be new OR </li> <li>The bacteria species must be changed OR </li>
 
<li> The range of utility must be enlarged </li>
 
</ul> <br>
 
The bacteria produced by the IGEM team will likely pass this test, because it is being
 
genetically modified to produce a strain of five enzymes the bacteria did not naturally
 
produce before. The Supreme Court’s decision in Diamond v. Chakrabarty confirms this
 
intuition. In Diamond, the patent-seeker had genetically modified bacteria to break down
 
crude oil, by incorporating multiple plasmids—each of which broke down a component of
 
crude oil—into one bacterium. The Supreme Court decided the new bacteria were
 
patentable, because it was a “non-naturally occurring manufacture or composition of
 
matter.” Instead of deciding that animate objects are simply non-patentable, the Supreme
 
Court decided that animate objects are patentable as long as that they perform functions
 
that they could not have done in nature absent human intervention. Incorporating five
 
enzymes into the DNA of a new bacterium—allowing it to generate Taxol, something the
 
bacterium had not done before—falls in line with Diamond’s holding27. IGEM’s genetically
 
engineered bacteria are fundamentally patentable, pending decisions on novelty and
 
nonobviousness. <br> <br>
 
Novelty is a tougher rung, but one that can still be met by genetically engineered
 
bacteria. As mentioned before, there are four ways novelty can be precluded as specified by
 
the America Invents Act:
 
 
<ul> <li>The product cannot have been patented before. </li>
 
<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
 
of filing the application.</li>
 
</ul>
 
<br>
 
The last requirement will not be a consideration here, as the product IGEM would claim in
 
the patent is the genetically modified bacterium, not Taxol itself. <br><br> <br>
 
With regards to the printed publication and public domain requirements, there is an
 
immediate irony that needs to be addressed. In In re Hall—considered by the United States
 
Court of Appeals For The Federal Circuit in 1986—the court held that a doctoral thesis
 
published in a library more than a year prior to filing, even when filed by the patent-seeker,
 
was a violation of the novelty requirement. In other words, if the IGEM team were to
 
publish the contents of the genetically modified bacteria more than a year prior to filing a
 
patent, patentability might be barred. There is a statutory exception, however, indicating
 
that you will not be barred if you file within one year of making the printed publication or
 
otherwise disclosing it publically. Once IGEM presents its work, the clock is ticking. <br> <br>
 
A cursory search of the Patent and Trademark Office database did not find anything
 
that would bar IGEM’s invention, in terms of prior patents. An internet search also did not
 
yield evidence that the bacteria engineered by IGEM is already in the public domain. <br> <br>
 
Non-obviousness is the hardest requirement for the IGEM team to fulfill. This
 
requirement asks whether or not another person with reasonable skill in the field could
 
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
 
genetically modifying bacteria to create new products is old science. Secondly, there are
 
other labs in the country also working to use bacteria in producing Taxol. In 2010, for
 
example, “U.S. and Singaporean researchers engineered strains of E. Coli that produce two
 
precursors of the cancer drug Taxol.30” The Massachusetts Institute of Technology was also
 
doing something similar in 201031. This does not make it impossible for IGEM to fulfill the
 
nonobviousness requirement—especially because the cited examples involve precursors,
 
whereas IGEM is using the bacteria to produce Taxol itself. The team’s lawyers would need
 
to argue to the PTO that the unique choice of enzymes to include in the bacteria to produce
 
the final Taxol product was a “creative leap,” not obtained by other researchers despite
 
tinkering with similar technology. <br> <br>
 
Ultimately, the utility, novelty and nonobviousness requirements can all be met with
 
regards to the specific genetically modified bacteria. The process of making that bacteria
 
would likely not be patentable due to nonobviousness requirement, but the bacterium itself
 
could be. The exclusive right to produce a bacterium that makes Taxol production more
 
efficient could be of immense value to a pharmaceutical licensee. </p>
 
 
<h2> Next Steps </h2>
 
<p> Through correspondence with Eric Wagner, an attorney in Duke University’s Office
 
of Licensing and Ventures, it is clear that the group itself does not have the rights to the
 
product. Rather, because Levine Science Research Laboratory facilities were used in
 
conjunction with a faculty mentor, Duke University owns anything created from the work.
 
Any filing for patentability and subsequent licensing would have to be done in conjunction
 
with Duke University, which could be a benefit given the University’s institutional
 
resources. If IGEM plans on patenting this bacteria, the next step should be meeting with
 
the Office of Licensing and Ventures, informing them of the product and negotiating with
 
them what licenses and royalties should ensue. </p>
 
 
<h2> Conclusion </h2>
 
<p> The Duke University IGEM team has created a new genetically modified bacteria
 
that produces Taxol more efficiently than past fermentation efforts using plant cells. In
 
order to expand the market supply of Taxol, licensing this bacteria to a pharmaceutical
 
company is almost essential, as is acquiring the patent to do so. Specifically, the mostlogical
 
patent would be on the genetically modified bacteria itself, which provides a
 
stronger case for meeting the patent requirements than other possibilities such as the
 
process or Taxol. <br> <br>
 
IGEM has to work with the University to license out the product to either a
 
pharmaceutical company or a non-profit. There is a trade-off: the former would be able to
 
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>
 
Should the patent be denied, the invention still has value. The best course of action in
 
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
 
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>
 
 
<h2> References <h2>
 
<p> STILL TO DO!!!!! </p>
 
 
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Revision as of 02:46, 19 October 2016