The Use of Ultra Long Patent Terms to Incentivize the Development of Novel Antibiotics

Introduction

Antibiotics are “substance[s] able to inhibit or kill microorganisms.”^[1] Antibiotic resistance is the process in which bacteria evolve through iterative generations to no longer be susceptible to a particular antibiotic compound.^[2] Through trial and error, random mutation, and epigenetic factors, bacteria will eventually become resistant to a given antibiotic.^[3] The fear that one day bacteria will no longer respond to any antibiotic therapies is not new, and unfortunately the grim concern has already been proven correct.^[4] Despite the importance and multiple failed initiatives to monitor and address the problem, very little progress has been made in the fight to combat antibiotic resistance, and the matter is projected to only get worse.^[5] Although modest patent term extension has been proposed, debated, and utilized to incentivize the development of novel antibiotics, innovators by and large have not rushed to develop more antibiotics.^[6] For the most part, the world still depends on a limited supply of around twelve classes of antibiotic compounds compiled since the 1920’s.^[7]

This paper proposes that radical ultra-long patent term extension could be used as a tool to combat antibiotic resistance. First, this paper will provide a brief history of the development of the various classes of antibiotics and the mechanisms or conditions that create antibiotic resistance. Second, it will assess some of the previous initiatives to counter antibiotic resistance through past legislation and forms of incentivization. Third, the paper will explore why the novel antibiotic market has failed. Fourth, a case for why ultra-long patent term extension may be a potential cure for such market failure will be discussed and the concerns that such a radical policy may raise will be addressed. Finally, the paper will conclude with policy recommendations rooted in the desire to spur competition and incentivize innovation.

I. Antibiotics and Antibiotic Resistance

A. Antibiotics in a Nutshell

Bacterial cells and animal cells belong to different domains of life. Species, such as staphylococcus aureus, are under the domain of Bacteria.^[8] In contrast, animal cells from the species Homosapien Sapien are classified under the domain Eukarya.^[9] Bacterial cells and Eukaryotic cells are fundamentally different. For example, eukaryotic cells replicate their DNA using tightly bundled chromosomes, and undergo the process of meiosis and mitosis.^[10] In contrast, bacteria have a single tangled loop of DNA that serves as the bacterial chromosome and undergoes replication via a process known as binary fission.^[11] As one might imagine, there are a host of specific proteins that serve as molecular machines which assist eukaryotes and bacteria to accomplish their objectives.^[12] Another stark difference between a bacterial cell and a human cell is the structure of the cell’s boundary. Human cells have a fluid mosaic plasma membrane primarily composed of a lipid bilayer (similar to drops of oil in water, but they are structurally supported with additional proteins and carbohydrate bridges).^[13] Bacterial cells, on the other hand, have rigid cell walls made up of protein and carbohydrates (similar to a gelatin pill capsule).^[14] Many bacteria utilize hybrid protein-carbohydrate molecules known as peptidoglycans as structural support for their cell walls, a characteristic not present in animal cells.^[15]

Antibiotics work by exploiting the molecular differences between bacterial and eukaryotic cells. Sodium hypochlorite, (household bleach) is excellent at killing bacteria.^[16] There are currently no bacteria that can survive extended exposure to bleach.^[17] However, there are no eukaryotic cells that can survive in the presence of bleach, either. Therefore, bleach makes for a poor antibiotic because it kills everything, just as an open flame would.^[18] The question then, is where does one look to find compounds that exclusively kill bacteria?

Molecules with antibiotic properties are typically found in nature.^[19] Certain animals and fungi produce antibiotic chemicals as part of their defense from bacterial infections.^[20] For example, penicillin was first discovered by Alexander Fleming in 1926 when he noticed certain molds were immune to bacterial growth.^[21] Later, Florey and Chain conducted experiments with penicillin on patients with bacterial infections.^[22] When they realized that penicillin can be used to treat bacterial infections, “Fleming, Florey and Chain shared the Nobel Prize in 1945 for their work which ushered in the era of antibiotics.”^[23]

It is essential to understand that different types of antibiotics exploit the various weaknesses of bacteria. Penicillin, Amoxicillin, and Flucloxacillin are antibiotics that belong to the class of beta-lactams.^[24] Beta-lactams work by disrupting the peptidoglycan cross linkage necessary for many bacteria to form their cell walls.^[25] Without a rigid cell wall, the bacteria explode from uneven osmotic pressure as water rushes into the leaky bacteria.^[26] Because human cells do not utilize a peptidoglycan cell wall, penicillin leaves the human cell unscathed and free to go about its business. Other classes of antibiotics such as sulfonamides inhibit bacteria’s ability to synthesize folate, an essential B vitamin.^[27] On the other hand, glycopeptides—the classification under which vancomycin is found, operate by blocking bacterial reproduction and thus halt the progression of infection.^[28] Despite the multitude of antibiotic compounds available, not all bacteria are the same.^[29] Some antimicrobial mechanisms are ineffective against particular strains of bacteria. For example, consider the distinction between gram-positive and gram-negative bacteria. Gram-positive bacteria have a “thick” coating of peptidoglycans surrounding their cell walls.^[30] Gram-negative bacteria, on the other hand, have a “high” concentration of lipopolysaccharides on the outer structure of their cell walls.^[31] Lipopolysaccharides and peptidoglycans have different properties and repel certain chemicals, similar to how oil and water do not mix. For this reason, penicillin and beta-lactams, which are effective against many gram-positive strains of bacteria, are almost ineffective at killing gram-negative bacteria because they cannot penetrate the protective lipopolysaccharide layer.^[32] Conversely, streptomycin, and tetracyclines, are able to kill gram-negative bacteria, but cannot easily pass through the thick peptidoglycan wall of a gram-positive bacteria.^[33] The takeaway from all of this is that not all drugs are effective against every kind of bug.

B. The Problem of Antibiotic Resistance

Drug-resistant diseases already cause at least 700,000 deaths globally a year, including 230,000 deaths from multidrug-resistant tuberculosis, a figure that could increase to 10 million deaths globally per year by 2050 under the most alarming scenario if no action is taken. Around 2.4 million people could die in high-income countries between 2015 and 2050 without a sustained effort to contain antimicrobial resistance.^[34]

Without a doubt, curbing the problem of antibiotic resistance is an important goal, but is it urgent yet? In the absence of an existential pandemic, there is not widespread demand for novel antibiotics. It follows logically that in the absence of demand, there will be an absence of incentive to further supply. The question becomes the following: when will we run out of antibiotics? No one knows for certain, and, at best, science can only speculate. What is confirmed, however, is that slowly, more strains of bacteria are outsmarting our drugs.^[35] The CDC has identified at least one species of previously susceptible bacteria that has acquired resistance to a member of a new class of antibiotics.^[36]

Other than depressing, the trend is indeed telling. For every commercialized antibiotic class thus far, there is at least one species of bacteria that has acquired resistance. Furthermore, there are three factors that will inevitably exacerbate the problem: (1) rapid bacterial evolution giving rise to antibiotic resistance; (2) continuing overuse and misuse of current antibiotics; and (3) the failure to develop a sufficient portion of novel antibiotics.

1. Rapid Evolution of Resistance

As mentioned above, most bacteria replicate through a process known as binary fission, where a single bacteria makes a single replica of itself.^[37] This form of growth is most simplistically modeled by the exponential equation $f(x) = 2^{x}$, such that f(x) is the number of bacteria, and x is the number of rounds of binary fission undergone.^[38] In the right conditions, “some bacteria like Escherichia coli can divide every 20 minutes. This means that in just 7 hours one bacterium can generate 2,097,152 bacteria. After one more hour the number of bacteria will have risen to a colossal 16,777,216.”^[39] The rate of reproduction is important because bacterial evolution is similar to the lottery: it’s a number’s game. Stated simply, the greater number of lottery tickets purchased, the greater your chances are of winning big.^[40] Although the mechanisms of bacterial genetics are far more complicated than described by a lottery analogy, the same premise and conclusion follow. Given the uncanny number of bacteria produced in such short time, with each new bacterium giving rise to the opportunity to gain resistance, eventually a resistant strain will emerge.

Sadly, a lottery model is actually a conservative representation as to the true nature of bacterial genetics. The lottery model illustrates the probability of resistance by a rare random mutation and multiplies that probability out by a large number of opportunities. In reality, it is far easier for bacteria to acquire antibiotic resistance. Despite being a-sexual, bacteria have the ability to pass genetic information to one another through a process called transformation.^[41] Similarly, bacteria can inherit genetic information from viruses in the process of transfection.^[42] To make matters worse, bacteria often carry small circular pieces of DNA separate from their single chromosome, known as plasmids. These plasmids may contain genetic information coding for antibiotic resistance and can be passed from one bacteria to another. Molecular biology laboratories routinely use plasmids containing resistance for a particular antibiotic to transfect and select for bacteria cultures carrying desired genes for expression.^[43] All of this simply means that in addition to randomly stumbling upon a genetic mutation that will give a bacteria antibiotic resistance, under the correct conditions, the bacteria can simply acquire a gene from a neighbor that yields the same result.^[44] So rather than a bacteria waiting to hit the lottery and becoming drug resistant, many bacteria can simply gain resistance from a neighbor and bypass the numbers game altogether; great for bacteria, bad for us.

2. Overuse and Misuse of Antibiotics

We are using too many antibiotics in too many inappropriate settings.^[45] As mentioned above, antibiotics are only effective against certain bacteria. Further, they are “ineffective” against viral infections.^[46] Viruses are fundamentally different than bacteria, as they lack many of the cellular mechanisms or requirements necessary for bacterial proliferation.^[47] Unlike bacteria, viruses are not living and they cannot be killed in the intuitive sense of the word.^[48] Bacterial cells are self-sufficient and are capable of self-replication. Given amiable conditions, bacteria will proliferate. In contrast, viruses are parasiticand can only proliferate via the host’s cellular “machinery.”^[49] These biological differences are important because mistaking a viral infection for a bacterial infection will result in a prescription of an antibiotic regiment. However, this regiment will do nothing to treat the illness and could give benign bacteria living in the patient the opportunity to develop resistance via exposure. Considering the similarities in symptoms between a head-cold (viral infection), and a sinus infection (bacterial infection), it is easy to see why a physician may either incorrectly prescribe an antibiotic, or may do so simply for good measure.^[50] Shockingly, studies show “[a]t least 30 percent of oral antibiotics prescribed in physicians’ offices, emergency departments, and hospital-based clinics are unnecessary.”^[51]

Despite physician prescriptions being a leading cause of antibiotic resistance, the livestock industry is also a significant contributor.^[52] Low-dose antibiotics are often administered to livestock to preemptively treat contamination from bacteria. Additionally, antibiotics are administered to promote the animal’s growth and final weight before slaughter.^[53] This practice is generally considered a misuse of medically important antibiotics.^[54] Internationally, there is a push to divorce medically important antibiotics from agriculture. For example, “[t]he practice of using antibiotics as growth promoters was outlawed by the European Union in 2006 and [by] the United States Food and Drug Administration in 2017.”^[55] The use of “medially important antibiotics” in the livestock industry prompted the United States Food and Drug Administration (FDA) to place further restrictions on such antibiotic use, and now requires oversight from the Center for Veterinary Medicine.^[56] However, groups such as the Natural Resources Defense Council have criticized the FDA’s initiative as being too vague in regards to details surrounding the phasing out times for such antibiotic use.^[57] Additionally, regulatory enforcement and compliance is far from uniform internationally.^[58] It is evident that international misuse of antibiotics in agriculture will continue to be problematic regardless of any policies adopted domestically in the United States because not all countries have adopted uniform conservation policies.^[59]

3. Failure to Develop More Antibiotics

The United States is not developing novel antibiotics fast enough. Table 1 summarizes approved and discontinued antibiotics from 2014 to 2019. The data shows that only 14 antibiotic drugs were approved by the FDA in the five year period between 2014 and 2019 whereas 17 drugs were discontinued in the same period. Although is the development of 14 drugs in only five years may seem promising, just how groundbreaking are these drugs? Many of the new drugs are combinations of old drugs or derivatives of previously successful antibiotics such as vancomycin. Table 2 lists the antibiotics approved from 2014 to 2019 along with their classifications, mode of action, resistance, and manufacturers.

As demonstrated in Table 2, even the most modern and groundbreaking antibiotics have strains of bacteria that are not susceptible to them. In all cases, such resistance is rare or only observed in laboratory setting. Regardless, a single instance of bacterial resistance is sufficient to prove that a resistance mechanism exists, and overtime, bacteria will evolve to exploit such pathways. The perspective to view the issue is not so much a matter of if we will run out of effective antibiotics, but instead, when. However, all hope is not lost.

Each novel antibiotic buys us time against the super bugs. Fetroja and Xenleta, both approved by the FDA in 2019, are particularly promising. Xenleta (Lefamulin) is effective against community-acquired bacterial pneumonia which refers to patients who become infected outside of a hospital setting.^[86] Xenleta is noteworthy because “[i]t is the first IV and oral antibiotic with a new mechanism of action the agency [FDA] has approved in almost twenty years.”^[87] Likewise, Fetroja (Cefiderocol) deserves similar recognition for its novel mechanism. “Cefiderocol is a novel antibiotic that works by acting like a Trojan horse. The drug acts as a siderophore, binding to ferric iron to penetrate the outer cell membrane of Gram-negative pathogens taking advantage of the bacteria’s need for iron to survive.”^[88] Surprisingly, neither of these drugs were made by American companies. Xenleta is made by Nabriva Therapeutics, a Dublin based company, while Fitroja is made by Shionogi, a company from Japan.^[89] The reality is that American drug developers are routinely shying away from investing resources to create new antibiotics. The multibillion dollar question is what can be done to curb antibiotic resistance?^[90] This question has raised serious concerns from both medical providers and industry, resulting in Congress acting numerous times.

II. Legislative Initiatives to Curb Antibiotic Resistance

A. The Hatch-Waxman Act

The Hatch-Waxman Act of 1984 was originally designed to encourage generic manufacturers to bring drugs to market.^[91] The act provided for the filing of an Abbreviated New Drug Application that would excuse a generic drug manufacturer from proving safety and efficacy with the same rigor as necessitated by a New Drug Application.^[92] To compensate the innovative branded drug makers, the Act awarded five-year data secrecy for information submitted to the FDA (that would otherwise be public) to keep innovator’s technology secret from generic companies.^[93] Additionally, innovators filing a New Drug Application are awarded patent term extensions for the duration of the time their drug is under FDA review.^[94] “The 1984 Hatch-Waxman Amendments excluded antibiotic drugs, which were then approved under FDC Act § 507, from the Act’s patent and non-patent market exclusivity provisions (except for the availability of a patent term extension).”^[95] In 2008, the Senate passed S. 3560, the QI Program Supplemental Funding Act, which was signed into law in October of that year.^[96] S.3560 extended the provisions of the Hatch-Waxman Act to new uses for old antibiotics approved before November 21st, 1997.^[97] The rational was to encourage and reward pharmaceutical companies for finding new ways to use the existing supply of antibiotics, but the result was re-patenting old antibiotics. As much as this conduct may shock one’s conscience and play into the narrative of Big-Pharma-up-to-no-good, perhaps there is more to the story.

Antibiotic use in the United States stretches back to the 1940’s.^[98] However, only recently has science progressed to the point where we can understand the molecular mechanisms underlying some of our drugs. “Knowledge gaps … [such as]… pharmacokinetics/pharmacodynamics (PK/PD), … exposure–effect and exposure–emergence of resistance relationships; … dose-finding approaches and optimizing dosing regimens, … susceptibility breakpoint setting[s], safety assessment and evidence-based therapy based on randomized controlled clinical trials” surround many of our old antibiotics when compared with their modern counterparts.^[99] With this in mind, perhaps it is wise to incentivize a second look at some old antibiotic compounds.

B. The G.A.I.N. Act

With increased concern surrounding the issue of antibiotic resistance, in 2012 Congress enacted the Generating Antibiotic Incentives Now or (GAIN Act) to further amend the Hatch-Waxman Act.^[100]

Sponsors who develop and submit applications for QIDPs [qualifying infections disease products] may be eligible to receive incentives through GAIN. The primary incentive contained in GAIN is that designation as a QIDP qualifies the drug for 5 years of marketing exclusivity to be added to certain exclusivity already provided by the FD&C Act. GAIN also makes drug products that have been designated as QIDPs eligible for Fast Track designation. FDA will grant Fast Track designation to a QIDP if requested by the sponsor. Finally, GAIN requires FDA to give priority review to the first application submitted for approval of a QIDP.^[101]

Medical professionals have not necessarily viewed GAIN as successful at inducing companies to innovate.^[102] Despite this, many of the antibiotics listed in Table 2. claim both new chemical entity exclusivity (NCE) and GAIN extension of that NCE activity.^[103] This shows that regardless of whether GAIN met its intended objectives of inducement, industry has not shied away from opportunities to increase their market exclusivity through the Act.

C. The 21^st Century Cures Act

With bipartisan support, former President Barrack Obama signed The 21st Century Cures Act on December 13, 2016.^[104] The piece of legislation contains multiple subchapters addressing interoperability,^[105] mental health initiatives, gene therapy, and personalized medicine. Title III “Development” contains four important subtitles, which are: Subtitle A—Patient Focused Drug Development, Subtitle B—Advancing New Drug Therapies, Subtitle C—Modern Trial Design and Evidence Development, and Subtitle E—Antimicrobial Innovation and Stewardship.

Subtitle A creates patient-focused drug development by allowing ‘patient experience data’ as acceptable evidence from sponsors seeking FDA approval of a new drug:

[T]he term ‘patient experience data’ includes data that- (1) are collected by any persons (including patients, family members and caregivers of patients, patient advocacy organizations, disease research foundations, researcher’s, and drug manufacturers); and (2) are intended to provide patients’ experiences with a disease or condition including—(A) the impact of such disease or condition, or a related therapy, on patient’s lives; and (B) patient preferences with respect to treatment of such disease or condition.^[106]

This change is a win for companies seeking new drug approval because it shifts a purely objective data standard to a slightly more subjective one, relieving some of the evidentiary hurdles they face.

Subtitle B permits new Drug Development Tools to be used as support in drug approval applications. “The Secretary shall determine whether to accept a qualification submission based on factors which may include the scientific merit of the qualification submission (emphasis added).”^[107] These tools are “any other method, material, or measure that the Secretary determines aids drug development and regulatory review.”^[108] One such tool is the use of surrogate endpoints. Surrogate endpoint means:

[I]mage, physical sign, or other measure, that is not itself a direct measurement of clinical benefit, and— (A) is known to predict clinical benefit and could be used to support traditional approval of a drug or biological product; or (B) is reasonably likely to predict clinical benefit and could be used to support the accelerated approval of a drug or biological product (emphasis added).^[109]

Again, this change allows for a more flexible standard and means that any measure that is reasonably likely to predict clinical results can be submitted in an application as opposed to the traditional “gold standard”^[110] double blind randomized clinical research trial. Physicians have raised concerns about the exact language of Section 3011, which they believe could give too much leeway and allow non-scientific data to undermine clinical data.^[111] However, there is also an argument to be made that prohibitively expensive double blind randomized clinical research trials are actually becoming obsolete in the face of “big data.”^[112] Artificial intelligence and predictive algorithms can track patient’s clinical outcomes via their electronic medical records, and, in the future, this may be a more effective way to conduct clinical research.^[113] Subtitle B of Section 3012 also promotes efficiency by allowing companies to leverage data from previously approved applications. This means that applications using very similar compounds, or applications that are combinations of known drugs will not require the sponsor to re-invent the wheel by providing safety and efficacy data on already known compounds.

Subtitle C—Modern Trial Design and Evidence Development- further broadens the type of acceptable data that can be filed in an application. Specifically, Section 3022 calls for the inclusion of ‘Real World Evidence.’ “[T]he term ‘real world evidence’ means data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than randomized clinical trials.”^[114] If not abundantly clear from Subtitle B, Subtitle C explicitly allows data to be included that are not derived from formal clinical research trials, raising the same concerns and possible benefits as mentioned above.

Finally, Subtitle E specifically addresses antimicrobial innovation and stewardship. Under Section 3041, all federal healthcare facilities are required to record instances of antimicrobial infection and resistance. The FDA is charged with monitoring these facilities and publishing public reports on their findings.^[115] In this portion of the Act, resources are also allocated to state agencies tasked with antimicrobial stewardship. Overall, these programs have been effective. On December 10, 2019, the FDA released their Annual Summary Report on Antimicrobials Sold or Distributed in 2018:

[D]omestic sales and distribution of medically important antimicrobials for use in food-producing animals increased nine percent between 2017 and 2018. Despite this increase, 2018 is the second-lowest year on record and the overall trend continues to indicate that ongoing efforts to support antimicrobial stewardship are having an impact: sales in 2018 are down 21 percent since 2009, the first year of reporting, and down 38 percent since 2015, the peak year of sales and distribution.^[116]

From these results in stewardship, it appears as though the 21st Century Cures Act is at least helping to dampen some of the leading causes of antibacterial resistance—that is misuse of antibiotics. But how does the Act incentivize the development of new antibiotics by drug innovators?

Subchapter E Section 3042 allows antibiotics (previously excluded) to be included for approval through a limited population pathway and is designed to incentivize novel antibiotic development.

The Secretary may approve an antibacterial or antifungal drug, alone or in combination with one or more other drugs, as a limited population drug pursuant to this subsection only if- (A) the drug is intended to treat a serious or life-threatening infection in a limited population of patients with unmet needs; (B) the standards for approval … are met; and (C) the Secretary receives a written request from the sponsor to approve the drug as a limited population drug pursuant to this subsection.^[117]

A limited population pathway is significant because it qualifies as an expedited form of application review. Also, the sponsor of the drug only needs to provide evidence that the drug is effective in a limited population, a much easier evidentiary threshold burden to meet as compared to acquiring approval for a drug suitable for a larger population. The antibiotic Pretomanid^[118] for the treatment of drug-resistant tuberculosis by the sponsor TB-Alliance, is the second drug to be approved under this new mechanism.^[119] Approval for Pretomanid came on August 14, 2019, less than three years from the enactment of the 21st Century Cures Act.^[120] This demonstrates that a limited population pathway is indeed attracting at least some sponsors to push through new antibiotics.

D. Shortcomings of Legislative Initiatives to Curb Antibiotic Resistance

The legislative efforts to combat antimicrobial resistance face two hurdles. The first is to reduce the spread of antimicrobial resistance. The second is to incentivize companies to develop more antibiotics to augment our current supply. As stated above, measures to prevent the misuse of antibiotics are taking root and, on their face, seem to be promising for the future. However, the second objective— getting new medications—is not effective. This will be further explored in Part III, The Market Failure for Novel Antibiotics, but for now, it is important to illustrate the primary fallacy of the legislation through an analogy.

Imagine the analogy of storming a medieval castle, compared to getting companies to create new antibiotics. No doubt, one who attempts to storm a castle must raise funds for an army and will then face many obstacles, such as a crocodile infested moat, a raised drawbridge, and arrows fired by the castle’s defenders from its walls. Analogously, a company attempting to develop a novel antibiotic must raise funds from investors, navigate regulatory agencies, bridge information gaps by conducting clinical research trials, and defend their product’s safety reputation by providing data to the relevant inquiring parties. In their most recent legislation on the matter, Congress has primarily focused on making the castle more vulnerable, that is by eliminating barriers. Congress has made provisions for new pathways to expedited review, relaxed the evidentiary requirements, and thus made it easier to get a novel antibiotic approved. The only problem is this, just because a castle is defenseless and easier to conquer, does not in and of itself justify a Queen to amass her resources and march on it. In fact, unless that castle serves a strategic advantage to the Queen, there is simply no reason to go through all the trouble to conquer it in the first place. The same can be said about drug developers. If there is not an enticing financial or tactical advantage to develop a novel antibiotic, why would anyone go through the trouble (and expense) to do so? This is where Congress has gone wrong, by failing to make the novel antibiotics market actually profitable. But who can blame them, and how could they make the market profitable in the first place? In light of big Pharma’s checkered reputation, what politician would have the courage to openly advocate for pharmaceutical companies to monopolize on medications as critical as antibiotics? The question remains: why is the antibiotics market not profitable?

III. The Market Failure for Novel Antibiotics

A. Branded versus Generic Dynamic

To understand the antibiotics market, it is necessary to first understand the branded and generic dynamic. Branded pharmaceutical companies are those that develop brand name drugs. Examples are Lipitor® made by Merck for high cholesterol, and Coumadin® made by Bristol-Myers-Squibb as a blood thinner. Branded companies typically file for patents on their medicinally active compounds and sponsor the drug through clinical trials for FDA approval. Once the drug is approved, it is sold at a high price for the duration of its patent term. At the expiration of the drug’s patent, the active compound is produced in mass by generic drug manufacturers and sold at a reduced price. For example Coumadin® is available as generic Jantovin®, but both contain the same active ingredient Warfarin. Generic drug manufacturers can sell at a reduced price because they do not have the overhead and burdens of research and development. Additionally, they are only required to file Abbreviated New Drug Applications as mentioned under the Hatch-Waxman Act. Naturally, branded pharmaceutical companies are highly incentivized to maximize the duration of their patent protection, and generic companies have every motivation to attempt to invalidate said patents. The sooner a generic company brings a generic to market, the sooner that company will make profits. Additionally, the Hatch-Waxman Act rewards the first generic company to file their Abbreviated New Drug Application with 180-day market exclusivity to further incentivize the production of cheap generics.^[121] Once a generic successfully launches, the branded company can expect for revenue on their drug to evaporate. “Often, a brand name drug can lose 80 percent or more of its market share in the first year in which it faces generics competition.”^[122] Antibiotics get no special exception. Any branded company that makes a novel and innovative antibiotic can expect to enter the same rat-race with any number of generic drug manufactures. The branded firms upon the development of any new antibiotic must be confident enough that their patents will not be held invalid, and that they can recoup enough profit through the sales of the antibiotic to justify the initial investment of development. Without a doubt, the stakes are high.

B. What Makes a Drug Profitable?

In the most simple of terms, there are three key variables that determine whether a drug will be profitable. They are (1) the initial investment spent on development and approval, (2) the price of the drug, and (3) the amount of drug sold. Pharmaceutical companies logically have a straightforward agenda, which is, first, to keep the initial investment as low as possible, second, to price the drug as high as the market will bear, and, third, to sell as much drug as possible.

On the first point, a branded pharmaceutical company can mitigate risk and lower expenses by purchasing emerging technology that has some likelihood of success rather than starting from scratch. Often times this is a common practice in the industry.^[123] However even with acquired technology, the average cost of bringing a drug to market is estimated to be far over a billion dollars.

The amount spent to develop any individual drug depends mostly on what it costs to conduct studies to prove it is safe and effective and secure regulatory approval. That can range from $10 million to $2 billion, depending on what the drug is for. But what really drives up costs is the fact that 90% of medicines that start being tested in people don’t reach the market because they are unsafe or ineffective. The … figure includes the cost not only of these failures, but also of not putting the money spent on them into something that would give a more reliable return.^[124]

Due to the unpredictable nature of whether or not a drug will be safe and effective, it is relatively difficult for a branded pharmaceutical company to cut costs on the initial investment of research and development and regulatory approval. This is why Congress has tried to relieve some of this burden through initiatives like the 21st Century Cures Act, as discussed above. However, there still remains the unaddressed second and third prongs of profitability.

A pharmaceutical company can only price a drug as high as the market will bear. If overpriced, neither insurance nor private payers will be able to afford the drug, and the company will lose sales. If underpriced, the company will lose potential revenue. An often neglected aspect of drug pricing in the sphere of public opinion is the fact that a drug’s price is not the result of the market forces behind that individual drug.^[125] Rather, the price tag on an individual medication represents the failed drugs that precede it and all other drugs the company is spending money to develop, plus their respective failures in those departments.^[126] The price must also allow the company to generate enough profit to hold themselves over (and maintain shareholder confidence) if they fail to find viable drugs for an extended period of time. Consider then, how high one could potentially price an antibiotic. If the infection is treatable with a common antibiotic, there will be no demand for a newer more expensive one, and the company could not justify charging more. To complicate the mater, a physician will rarely skip using lower strength antibiotics in favor of immediately using a stronger one, even if the stronger antibiotic is more effective. Doctor are encouraged to prescribe the minimal antibiotic regiment that will resolve the infection regardless of what a patient may request.^[127]

The most significant barrier preventing novel antibiotics from being profitable is the fact that a pharmaceutical company simply cannot sell enough of the drug at a sufficient price during the lifetime of their patent. A typical antibiotic regiment lasts “7 to 14 days.”^[128] Contrast this to a lifetime prescription of high blood pressure medications, month long chemotherapy regiments, or daily anti-anxiety or depression medications. To make matters more complicated, it is entirely possible that a patient’s own immune system could shake off their infection absent any therapy at all. A pharmaceutical company seeking financial stability is more likely to prevail by investing in drugs that patients will buy throughout the duration of the patent, rather than one-to-two-week regiments to cure a rare infection. The only way to recover sufficient revenue with such short treatment cycles is naturally to charge an exorbitant price, but then the company runs the risk of insurance not willing to pay, and the patient ultimately recovering while on a prolonged treatment of weaker antibiotics. On all three prongs of profitability, antibiotics strike out. To make matters worse, the whole point of fighting antibiotic resistance is to curb the use of antibiotics in the first place.

C. Patents and the “Antibiotic Paradox”^[129]

In 2009, Schulman summed up the antibiotic patent paradox nicely when she wrote: “[T]he antibiotic developer, often a private corporation, has an incentive to maximize its economic benefit [during their patent term] despite any negative effect on antibiotic resistance … in attempting to maximize profit, the antibiotic developer encourages the overuse of the antibiotic and increases the likelihood of antibiotic resistance.”^[130] Schulman ultimately concludes that patents and reliance on the private sector is fundamentally inadequate to remedy or at least curb the problem of antibiotic resistance, and she calls for direct government involvement in the development of antibiotics.^[131]

As the law currently stands, Schulman’s words ring true, and there may be some merit to her proposed solution. Overwhelmingly, sponsors of new innovative drugs are branded pharmaceutical companies that are profit driven, risk adverse, and not entirely altruistic. Additionally, the real world example of TB-Alliance provides some support for public funding to develop antibiotics. TB-Alliance, the maker of Pretomanid for drug-resistant tuberculosis, “is a not-for-profit product development partnership … between the public, private, academic, and philanthropic sectors to drive the development of new products for underserved markets.”^[132] Despite this, it is important to consider the realities of antibiotics approved in the past five years. Thirteen of the fourteen, or about 93 percent of new antibiotics were developed by private industry, and TB-Alliance is both funded and comprised of members form the private sector. One thing is for certain, drug developers are best suited to develop drugs, just as inventors are best suited to invent. The real question is how can society incentivize someone to invent new antibiotics?

Antibiotics are persnickety things. They are hard to discover, harder to invent, and the disease they intend to remedy can mutate quickly rendering them ineffective. Worse yet, antibiotic resistance is a direct result of using antibiotics in the first place. A fitting analogy is like trying to throw darts at a dart board, that is continuously moving left to right, and every time you hit it, it moves ten feet further back. Oh, and the round of darts costs about a billion dollars so you best not miss. Creating a novel antibiotic is truly a gamble, and pharmaceutical companies are increasingly choosing not to play. Those companies who do play and lose, lose very badly. Consider the makers of the fourteen approved antibiotics since 2014, depicted below in Table 3.

As shown above, companies that have only focused on developing antibiotics have not fared well in the past five years. Such companies have either been acquired, filed for bankruptcy, or on average lost nearly 90 percent of their stock’s value. These negative outcomes are in the backdrop of the strongest economy America has seen in approximately 40 years.^[140] It is safe to conclude the antibiotics market has failed. Although a handful of antibiotics will continue to trickle through the development pipelines, companies as rational and prudent actors would be wise not to invest significant portions of their resources in further development of these drugs. Despite the necessity of developing novel antibiotics for the public, the current market and regulatory structure fails to incentivize pharmaceutical companies to satisfy those needs unless a radical change is made.

IV. Ultra-Long Patent Terms for Novel Antibiotics

The idea of passing legislation to incentivizing industry to develop more antibiotics is by no means new. Such efforts are found in the Hatch-Waxman Act, the GAIN Act, and the 21st Century Cures Act. Despite these laws, companies in the last five years have developed antibiotics at their own peril. What follows is a brief discussion on previously proposed incentives and their shortcomings, along with an argument that ultra-long patent term extensions may be the long sought-after solution to the antibiotic paradox.

A. Why Tax Incentives Alone Are a Bad Idea

Tax incentives can be used in two ways to curb antibiotic resistance. First, by either providing tax breaks for companies that dare to continue research and development in this field, or, second, by taxing the use of antibiotics as a disincentive for frivolous misuse and over-prescription. Both are bad ideas.

The government provides tax breaks for non-economically sound behaviors it wishes to encourage.^[141] This can be seen in the tax breaks associated with homeownership, the number of children dependents, and through tax deductions as a result of donations to 501(c)(3) non-profit organizations. For example, a young couple who is paying rent for an apartment but has no debt is rewarded with a tax incentive to enter into the economically unsound activity of purchasing a $230,000 home on a thirty-year mortgage. Although many people purchasing a home think it is an asset, for the majority of single-house homeowners who also live in their homes, the purchase is more akin to a liability when taking into account the cost of furnishing and maintaining the home.^[142] Similarly, because we no longer live in a society where children are useful as sources of labor, having a child from a purely financial stand point tends to diminish resources with little to no expectation of recoupment on investment.^[143] Additionally, no explanation is required to understand why simply giving money away to non-profit organizations is a poor investment. The takeaway from all of this is that tax incentives do not make the underlying activity more profitable. Instead, they are designed to slightly ease the pain of the bad decision. The same is true of tax incentives to develop antibiotics. Just because a company pays less in taxes for engaging in the unprofitable behavior does not mean they will be able to sell more antibiotics or charge higher prices for those they are able to sell. Furthermore, unless tax incentives are narrowly tailored only to offset costs for novel antibiotic development, the tax break is likely to incentivize tokenism behavior.^[144] If a company can get broad tax incentives from a half-hearted antibiotic development program, then that’s exactly what you’ll get: half-hearted antibiotic development. This is actually antithetical to what society needs. Society does not need slightly different or equally effective new antibiotics; we need significantly new and groundbreaking antibiotics coming down the research and development pipelines. Anything less than that and taxpayers are being done a disservice, but what about a tax penalty?

Almost 15 years ago, in his piece about antimicrobial resistance, Kades discussed the concept of a “tax that forces those creating such external costs [on society] to ‘internalize’ the burdens they impose on others. These are called Pigovian taxes, in honor of A.C. Pigou, the first economist to discuss such a measure formally.”^[145] In this case, those who use antibiotics for medical or agricultural purposes would be taxed as a penalty for the cost society pays for these behaviors that increase the likelihood of antibiotic resistance. Today, Kades’ conclusion still holds true, “higher prices would lead those with mild infections … to refrain from using antibiotics. This is precisely what the tax is supposed to do: push those who value antibiotics the least out of the market.”^[146] However the Pigovian tax only addresses the first step to curbing antibiotic resistance, that is by disincentivizing misuse. Such a tax does nothing to address the second step of developing new antibiotics, and actually would make antibiotics an even less profitable endeavor for pharmaceutical companies. Not only is the drug more expensive, thus disincentivizing sales, but the added expense generates no additional revenue for the manufacturer, thereby killing the product’s profitability. For these reasons, tax policies are not likely to turn the tide in novel antibiotic development for failing to make such drugs profitable. If tax policies cannot help, what will?

Patent Terms

Patents hold a special place in hearts of pharmaceutical companies. In few industries are patents more critical to the commercial interests of their holders than in the life-science and biopharmaceutical space. As discussed in Part III.A., the validity of a drug patent can make the difference of billions of dollars of revenue for a company. Additionally, if a patent is held invalid after the company has received FDA approval, this will result in a loss of most of the initial investment to develop the drug in the first place. It follows that most, if not all, of a drug’s profitability is tied to its respective patent portfolio. Hence, if Congress is seeking to make the development of antibiotics profitable for a pharmaceutical company, the place to start is the patent term.

B. Moderate Patent Term Extension

With the above logic in mind, Congress did in fact increase patent terms multiple times. As Schulman points out,

laws such as the Hatch-Waxman Act and the Best Pharmaceuticals for Children Act [(BPCA)] allow the extension of the patent term for pharmaceutical inventions in certain circumstances. … Both … [acts] … lengthen the patent term for certain pharmaceutical patents, while the Orphan Drug Act grants a seven-year market exclusivity for a qualifying drug. These Acts do not differentiate between antibiotics and other types of drugs.^[147]

Under the premise that these statutory patent term extensions do not discriminate based on drugs, and that more antibiotics were not being produced despite their passage, Schulman concludes that such patent term extensions fail to incentivize the development of new antibiotics.^[148] Schulman further argues that even if the terms were extended longer than what is currently available, because bacteria can mutate and acquire resistance so quickly, they would likely gain resistance before the expiration of the extended patent term, thus defeating the whole point in the first place.^[149] However, the author’s argument may have gone too far.

First, although moderate patent term extensions have not made antibiotics profitable, that is not the failure of the concept of the patent term extension itself, but rather a failure of properly applying a patent term extension specifically tailored to antibiotics. Schulman may correctly state that previous legislation did not specify antibiotics, and failure of Congress to consider the realities of antibiotic resistance is why the Act was too broad to be effective for antibiotics. Critics of patent term extension for antibiotics could also point to the GAIN Act and claim that this specific patent term extension directed towards new antibiotics has also failed to make them profitable enough for industry to be incentivized to develop in this space. However, consider how long the GAIN Act actually extended patent protection for qualifying antibiotics: only five years.^[150] Five years in addition to the regular patent term is simply not enough time to recoup the investment of selling drugs that are supposed to be used conservatively. If it were, we would have seen an explosion of development in this area that has not yet come.

Second, the fact that a single bacterial strain acquires antibiotic resistance does not render the antibiotic non-beneficial. There are multiple strains of bacteria that are resistant to penicillin, but more importantly, there are far more strains that are still susceptible.^[151] Even if a bacteria is immune to a novel antibiotic, this does not mean a patent term extension has proven useless. That novel antibiotic may still be able to defeat other previously untreatable infections, that absent such an extension, the company would never have chosen to invest in such an antibiotic. Ultimately, what is known about modest five year patent term extensions through the GAIN Act is that industry does not think they are enough to justify the financial gamble associated with antibiotic research and development.^[152]

C. Wild-Card Patent Term Extensions and Why They Could Be Ineffective

In 2009, Sonderholm proposed a different type of solution to the antibiotic paradox.^[153] To decrease the risk associated with a pharmaceutical company’s gamble developing antibiotics, Sonderholm proposes that Congress give them a wild-card. “‘Wild-card patent extension’ is the name commonly attributed to the idea that a pharmaceutical company that introduces a new and effective antibiotic on the market should be allowed to get an extension on its patent-rights for one of its other products.”^[154] Solderholm makes a compelling argument as to the cost effectiveness of such a plan and identifies fairness as the primary concern with increasing the patent life on an already widely used blockbuster drug. In other words, “people who need [the] drug will have to pay an artificially high price for [the] product for an extended period of time.”^[155] Although this is indeed unfair, what is more concerning that Solderholm fails to address is the tokenism problem.

Why would a pharmaceutical company invest significant resources to develop an antibiotic, if the sole incentive to do so is just to get a patent term extension on one of their most profitable drugs? The answer is they likely would not. In fact, from an economic perspective, the company would be incentivized to do the absolute bare minimum to still be able to obtain the wild card extension. This will drive up costs on current patented drugs, and not necessarily deliver sufficiently innovative new antibiotics. The hypothetical antibiotic would not even need to be novel enough to receive a patent, because as long as it is new to the market, the company could claim a patent extension reward for their other blockbuster drugs. Of course, Congress could anticipate this issue in their legislation, but now you would be asking Congress to predict and gauge how new a new antibiotic actually is. This is far beyond the purview of Congress and opens the doors to litigation when an antibiotic, patented or not, is deemed by an agency not new enough to garner the reward. Furthermore, the fact that a company would have to spend resources only to be told their product doesn’t qualify would throw a wet blanket on the entire incentive in the first place. Wild-card patent term extensions are destined to fail because they fall into the same fallacy as tax incentives: they fail to make antibiotics themselves profitable. So the question remains, how can an antibiotic actually be profitable?

D. The Case for Ultra-Long Patent Terms

Recall for a moment the prongs of profitability: low initial investment, maximum allowable price, and maximum sales. The only way to make a drug more desirable to develop is to make it more profitable for the developer. On the first prong, Congress has already made it easier to get approval for antibiotics, but still this does not make them worthwhile to develop. Antibiotics are only able to generate profit when they are sold. The problem is that we do not want them to be sold too quickly, lest bacteria rapidly develop resistance. One solution is to extend the patent term to some length so that a company will slowly be able to recoup their investment over the long term.^[156] Consider the hypothetical antibiotic such that over the course of a regular patent term with GAIN extension, a pharmaceutical company would be able to sell 1,000,000 prescriptions. Now, imagine that physicians prescribe the drug conservatively such that they only recommend the drug be used in one out of every ten cases they see. This means that given the same number of years in the patent term, the company will only be able to sell 100,000 prescriptions, exactly one tenth of their predicted sales.

To solve this problem, the pharmaceutical company has two options, one is to raise prices tenfold to recoup their lost potential sales due to the rarity of prescription. However, this further disincentivizes a doctor from prescribing such an exorbitantly expensive medication, this diminishes the likelihood insurance will cover the costs of the drug, and this makes it less likely a patient would be willing to pay for the drug out of pocket. Therefore, raising the price of this hypothetical antibiotic is a losing strategy. A second option is to simply stop making antibiotics and focus on other types of drugs that are not conserved; this is where we are today. But what if there was a third option? What if the patent on that hypothetical antibiotic was extended ten-fold such that, at the conservative prescription rate, the company would have the opportunity to make their expected profits at a reasonable price, just over a longer period of time? This is the case for ultra-long patent term extensions to make novel antibiotic development profitable.

Immediately, there are obvious concerns to such a plan. First, who is to say that a pharmaceutical company will slowly sell their novel antibiotic and refrain from vigorous marketing to maximize the sales of their new drug?^[157] However, it is important to pause for a second and consider the following. If we are asking the question how will we keep pharmaceutical companies from marketing their new antibiotics, we are already moving in steps in the right direction from asking how can we get new antibiotics. If big pharmaceuticals were incredibly effective at marketing and selling new antibiotics, then why are they not already doing this? Why aren’t antibiotics just as profitable as any other drug? The latter question is answered in Part III, and it sheds light on why a pharmaceutical company simply cannot cheat and oversell. Doctors still hold the power to prescribe antibiotics. If it were up to patients, they would likely take any medication they believed would make them feel better.^[158] However, doctors act as the gatekeepers when it comes down to when and what to prescribe. The pharmaceutical companies cannot cheat and bypass this system. They can, however, encourage doctors to prescribe their drugs, and what better way to do this than by charging reasonable prices, creating more effective compounds, and having development programs that ensure a steady supply of new antibiotics?

Another concern is how long should these ultra-long patent terms be in the first place? If a 20-year patent term was extended tenfold, that means we would be looking at a 200-year long patent term, which is clearly unreasonable. But what about a 70-year patent term? First, consider that the origin of the patent term is relatively arbitrary in the first place.

Nordhaus, for instance, expressed a rather cynical view on the way in which the US government has decided on its previous patent term of 17 years. Quoting Machlup’s reference to the past-1624 English patent term of 14 years that was based ‘on the idea that 2 sets of apprentices should, in seven years each, be trained in the new techniques’, he concludes that in the USA it was decided ‘that 2.43 apprentices, or 17 years, would be the proper length.’ ^[159]

The modern U.S. utility patent term, 20 years from the effective filing date, also seemed like the right amount of time to grant market exclusivity to compensate an inventor for their disclosure to society.^[160] This is key. If the patent term is no longer adequate to compensate a particular kind of inventor for a particular type of discovery, then doesn’t this mean the patent law is no longer fulfilling its purpose?^[161] If the whole purpose of patent law is a quid pro quo between society and inventors, and if society is not holding up their end of the bargain by adequately compensating inventors, shouldn’t we logically expect inventors to not be pursuing these inventions? Is this not the very phenomena we are currently witnessing in the antibiotic industry?

When the founders wrote the Constitution, they never specified exactly how long a patent term should be other than “for [a] limited time.”^[162] Although America adopted the English model of a fixed term, they could have just as easily adopted a French model which stated: “… there shall be delivered to him a patent for five, ten or fifteen years.”^[163] As evident from the early French patent system, a universal patent term does not necessarily make sense because not all industries are the same and neither are any two inventions. Further, not all intellectual property seems to be valued the same by society. Even in American intellectual property law, varying intellectual property value is evident in the fact that design patents are only awarded 15 years of exclusivity as opposed to a utility patent that garners 20.^[164] Does this suggest that some patents are more important than others, or rather that a utility patent is more useful to society than a design patent? Are utility patents all of equal societal value? If so, then why do salty tasting fishing lures to catch bass get the same patent term as an anti-viral medication used to treat multi-phenotypic drug-resistant hepatitis C?^[165] The answer is that the hepatitis medication is valued more by society than the fishing lure, as evidenced by Congress giving the medication the option for patent term extension under the Hatch-Waxman Act and not extending the same benefits to fishing lures. This means that Congress understands the unique challenges associated with drug discovery, and even recognizes the peculiar circumstances that surround antibiotics as evidenced by the provisions in the GAIN Act and 21st Century Cures Act. With this in mind, it does not seem unreasonable for Congress to carve out a special ultra-long patent term for antibiotics, given the arbitrariness of the patent term in the first place, and the unique role antibiotics serve in society. So if five-year patent term extension was not enough under the GAIN Act, then what would be?

To gauge an appropriate patent term, first consider why market exclusivity is granted in the first place. Market exclusivity is designed to allow an inventor to maximize their profits in absence of any competition. The absence of competition allows for a price higher than that which would be present in a market where the inventor would have to price competitively. This artificially high price, reflected as a deadweight loss on society, is the money reward bestowed to an inventor for the disclosure of their invention.^[166] This reward is designed to make inventing, and subsequently disclosing the invention via the patent system, more profitable than simply mass producing existing goods, and thereby is intended to encourage innovation. Naturally, the longer the patent term, the longer the inventor would be allowed to charge the artificially high price. However, just because a monetary reward exits does not mean it will be rewarding, as illustrated by the following hypothetical.

Consider for a moment that you are in a two hundred acre field full of hay, and someone tells you that they will pay you five dollars to find a blue marble that they dropped somewhere in the field. Would you do it? For most of us, the answer would be a resounding no. The feat would be so time consuming and onerous that the five dollar reward simply is not enough for the trouble. Also, imagine the opportunity cost of spending hours, possibly days, walking the field and looking for the marble which you may never find despite your best efforts. But what if someone offered you $90,000 for the same task? For many, this reward would significantly alter their decision. If the searcher only makes $45,000 a year doing their routine day job, even if it takes them a year to find the marble, they still double their money. Furthermore, that single searcher may enlist friends and family to assist them in their prospecting. But what if the reward was raised to $1,000,000,000? Rest assured, the marble will be found. For one billion dollars, there is enough of an incentive to encourage investors to buy 2,000 drones, design an artificial intelligence software to spot blue reflective surfaces, equip the drones with said software, and have each drone scrutinize a tenth of an acre for days until one of them finds the marble.^[167] To summarize, the hypothetical illustrates three principles: (1) a monetary incentive must be at least worth more than the cost required to obtain it; (2) a monetary incentive must be at least equally profitable as the typical non-incentivized behavior; and (3) the greater the reward, the more creative lengths a potential recipient will go to obtain such a reward. These rules apply directly to the antibiotic market, and the analogy couldn’t be more fitting. Finding a safe and effective drug is similar to finding a marble in a hayfield and so far, pharmaceutical companies are choosing not to look.

So what should the patent term be? The patent term of an antibiotic should be considered the monetary reward paid to an inventor or patent owner for the discovery and commercialization of the drug. The reward is governed by the three prongs of profitability: low initial investment, maximum price, and maximum number of sales. The reward is also subject to the three rules of incentivization discussed in the preceding paragraph. A pharmaceutical company has practical limitations on how low their initial investment can be. First, it is impossible to know how many failed attempts will come before identifying a pharmacologically effective compound. Additionally, despite the relaxed requirements for evidentiary showing to get approval under the 21st Century Cures Act, it is impossible to predict if a drug will actually receive such approval. Furthermore, despite the seeming total power of a pharmaceutical company to raise prices arbitrarily, this too has limitations. The price is determined by the market. If a pharmaceutical company prices too high, even patients who need the drug cannot afford to purchase it. Stated another way, if insurers think a price is unreasonable, they will deny coverage. If insurers and patients refuse to pay for a medication, doctors will be disincentivized to prescribe it. In the case of antibiotics, this effect is even more pronounced because novel antibiotics are already used as alternatives to failed regiments of conventional antibiotics. Thus exorbitant prices on novel antibiotics promotes greater reliance on cheaper conventional ones.

Maximum number of sales, the final prong of profitability, becomes critical in any incentivization model. If a company cannot control initial investment, and has practical caps on the price they can charge, the only way to maximize profits is through the number of sales of their product. However, doctors are reluctant to prescribe antibiotics liberally, and rightly so. Liberal administration of antibiotics in fact is a leading cause of antibiotic resistance. But consider the following: conservative prescription of antibiotics only means slower sales, not necessarily less sales. More and less are both relative terms, and when applied to sales, they depend on the respective timeframe of the selling period. For example, the sale of 20 units has very different meanings if the time frame is 20 minutes, versus 20 years. For innovative pharmaceutical compounds, the timeframe for sales is the portion of the patent term after the drug has received approval, and this timeframe must be in accord with the rules of incentivization to make the drug profitable and be worth the trouble to develop.

On the first prong, a monetary incentive must be at least worth more than the cost required to obtain it. In the case of antibiotics, this means that at minimum, the pharmaceutical company must be able to get a full return on investment sunk in development and approval as a threshold requirement. That is, if the company cannot at least break even, there is a negative impetus and disincentive to innovate. Consider for example the drug Dificid, for the treatment of C. difficile. “Dificid was approved in 2011. It commands a premium price for an antibiotic - about $3500, vs $1500 for vancomycin or $10 for metronidazole, the current first-line treatments for C diff infections. Sales for Dificid appear to be around $70M/yr.”^[168] Assuming it cost at least 1.5 billion dollars to bring Dificid to market (an average of one- and two-billion-dollar estimates), it would take approximately 21 years of sales to break even. But Merck, the company that now sells Dificid, acquired the product after purchasing Cubist Pharmaceuticals who had previously acquired the drug from Optimer Pharmaceuticals.^[169] Thus Merck is able to enjoy profits from sales of this antibiotic without having to invest in the initial research and development. Granted, Merck still paid something for the initial acquisition of Cubist. What all of this means is that pharmaceutical companies likely can at least break even on investment given the current patent terms, but the question is why would any company set the standard at just breaking even? This leads to the second prong of incentivization.

A monetary incentive must make the behavior at least equally profitable as the typical non-incentivized behavior to encourage the desired result. This is the key problem responsible for why companies resist developing new antibiotics. Returning to the case of Dificid:

Sales for Dificid appear to be around $70M/yr. That may sound like a lot, but it’s couch cushion money at Merck (total sales ~$40B/yr). To a first approximation, the risks and costs of developing Dificid were the same as for Keytruda, a targeted therapy for solid tumors. Keytruda sales are $1.4B per year, 20 times that of Dificid. Same risk, 20X reward.^[170]

Given the preceding information, it is not surprising companies choose not to invest in antibiotics. Why invest in antibiotics when other fields such as oncology, statins, and blood glucose controls can make the company twenty times in sales? Ultimately, why should a company knowingly invest in a medication that by the nature of the patent term will never achieve blockbuster status?

The company should not have to invest and they will not. Health policy and conservation mechanisms are responsible for the conservative prescriptions of antibiotics and thus lower sales and return on investment. Additionally, a bacterial infection is typically an acute condition versus a “chronic disease” like diabetes, this naturally drives down the drug’s profitability by limiting the amount of drug that can be sold to each individual patient.^[171] Therefore, the solution to incentivizing novel antibiotic development is simple. If antibiotics were as profitable as other blockbuster drugs, pharmaceutical companies would be incentivized to develop them.

So if the patent term post approval is the amount of time a company can sell a drug and make profit, how long would the term need to be to make antibiotic sales at their conservative prescription rate, as profitable as current blockbuster drugs?

Given the data from Table 4, the average sales of the top 10 blockbuster drugs is $8.74 billion. However, given that Humira brings in at least $10 billion more than other any other drugs, performing a Grubb’s Test reveals the following data.

The data in Table 5 reveals that Humira is a statistical outlier and should be excluded from the calculation of the average blockbuster drug. From the other nine, that average becomes $7.5 billion. Therefore, the most profitable drugs, on average, bring in $7.5 billion in sales. This means that the appropriate patent term to truly incentivize the development of antibiotics is however long it would take for a company to earn about seven and a half billion dollars from sales of that antibiotic.

An interesting example is Azithromycin, an antibiotic owned and distributed by Pfizer under the name Zithromax. “Pfizer’s branded version of Azithromycin - was one of the best selling branded antibiotics in the United States and worldwide, with total sales peaking at US $2 billion in 2005 before starting to decline with the loss of patent protection in 2006 and resulting generics competition.”^[172] Because Zithromax was developed before extension available under the GAIN Act and the Uruguay Round Agreements Act, the maximum patent term that could possibly be enjoyed was 17 years.^[173] Through simple proportional analysis in Equation 1:

The proportional analysis demonstrates that it would take approximately 63.75 years for an antibiotic as successful as Zithromax to achieve modern day blockbuster status.

Clearly some assumptions are made to arrive at this figure, but stricter analysis would likely make the number larger. For instance, only one antibiotic was selected for the proportion as opposed to an average range, like the one used to determine blockbuster status. Despite this, the point of incentivization is to get globally successful and effective antibiotics to market, so it does not make sense to factor in less successful antibiotics because those are not the standards wished to be promulgated. Also, less successful antibiotic sales would actually increase the time it would take to reach block buster status. Furthermore when attempting to incentivize under the last prong of incentivization, the greater the reward, the more creative lengths a potential recipient will go to obtain such a reward. Thus steps to limit the calculation actually prove counterproductive to the objective of incentivizing novel antibiotic development. In reality, the theoretical number of years to achieve blockbuster status is actually greater than 63.75 years. Recall that the United States has been late to limit the use of antibiotics, and only since the 21st Century Cures Act has Congress required formal data reporting on the prevalence of antimicrobial resistance. This means that during the patent life of Zithromax, prior to 2006, the drug was likely prescribed by doctors far more liberally than it would be prescribed now. This indicates that if the drug were subject to the same scrutiny and precautions modern antibiotics face, its sales would likely have been lower, meaning it would have taken longer to reach blockbuster status. The ideal patent term to incentivize novel antibiotic development is therefore likely between 63.75 and 70 years.

E. Why Private Patent Rights are Ideal to Solve the Antibiotic Problem

Patent law by its very nature is designed to limit the use of a patented article to the patentee. This general limitation on use is an excellent means of asserting control, without creating additional regulatory oversight. Stated another way, Title 35provides standing for any patentee to sue companies or individuals that are infringing the claims of their patent in federal court.^[174] At its essence, Title 35 creates a mechanism for private actors to police and assert their own patent rights. When applied to antibiotics, this means a company will be able to limit the ease of access to their patented antibiotics, preventing wide spread use and resistance to said antibiotics. Enforcement of patent rights provides one additional way antibiotic resistance can be curbed, which does not require action from the CDC, FDA, or NIH. Ultimately, the patent right creates a unique set of private interests that are helpful in curbing antibiotic resistance.

There are benefits to keeping antibiotic development in the private sector by means of lengthening patent rights. First, the tokenism problem is resolved by incentivizing antibiotic development through tying profitability to the antibiotic itself, as opposed to offering tax breaks or wild-card patent term extensions. The antibiotics put forward must be of sufficient therapeutic benefit to justify being prescribed over more conventional and cheaper antibiotics. This incentivization scheme reduces the likelihood of pharmaceutical companies investing in antibiotics that offer slight benefits over analogous therapies, in favor of pursuing compounds that offer radical benefits over competitor’s products.

Second, long-term patent rights for antibiotics may allow start-up companies to obtain funding. As evidenced by the data in Table 3, the current financial outlook for companies seeking to exclusively grow in the antibiotic space is grim. Long-term patents will allow investors to maintain confidence that these companies will be able to eventually turn a profit. However, if the company still cannot generate profits, the fact that their patent lasts longer will create more value in the event that the company is forced to sell or license their IP rights. Ultimately, the prospects of more profitable patent rights for antibiotics will increasingly motivate researchers to pursue this area of study

Third, by tying private financial risk to the development of each new antibiotic, this incentivizes research to be done in the most cost-effective manner. With the United States national debt already over 23 trillion dollars, it is fair to say the federal government is not excellent at conserving taxpayer money.^[175] Given the high failure rate and technical nature of drug discovery, the federal government nor its agencies should be tasked with developing novel antibiotics.

Fourth, contrary to the conclusions reached by Schulman “direct governmental action,” is not the best way to develop novel antibiotics, because such intervention would not be likely to save money, nor produce superior antibiotics.^[176] To fund large scale antibiotic development that does not rely on the private sector would still require the same costs incurred by any private pharmaceutical company doing similar research. What this means is that research conducted in government facilities is not necessarily any cheaper than research conducted in private laboratories. Any costs that would have originally been incurred by a private corporation are simply transferred to the tax-payer. If the government tries to hire contractors to conduct their research, then society is in a worse position than before. Rather than having a company take on financial risk and be incentivized to succeed, the government would simply be writing blank checks to a company, who by contract, would be compensated regardless of the results obtained. To further exacerbate this problem, if antibiotics are in fact developed, the federal government would still need to rely on the private sector to create medications on scales large enough to serve the population. The process of ensuring that multiple tiers of contractors are complying with regulatory and safety guidelines would create massive amounts of expense and inefficiencies. This is not even considering the implications or costs of performing clinical research trials of any compounds that would be developed via this hypothetical government-orchestrated pipeline. Finally, in such a world where the government was able to develop a novel antibiotic, test the antibiotic for safety and efficacy, get approval from the FDA, and bring it to scale to serve the population, what happens if the drug causes unforeseen long-term side effects? Who would remain financially and legally liable to harmed patients? Would citizens be allowed to bring a class action mass-tort case against the federal government? What would the recourse be for people harmed that are not U.S. citizens?

Conclusion

Despite the internationally recognized need for antibiotic development and conservation, pharmaceutical companies are seeking not to invest in novel antibiotics due to their lack of profitability. Drugs that meet the following conditions are profitable: 1) the initial investment is low, 2) the drug is sold at the maximum possible price, and 3) the number of sales are maximized. Congressional initiatives to stimulate novel antibiotic development have largely failed because they do not create a framework in which antibiotics themselves can be profitable. Instead, initiatives codified in the 21st Century Cures Act, the GAIN Act, and the Hatch-Waxman Act have focused on expediting approval and attempted to reduce initial investment costs, only one out of the three factors that account for the profitability of a drug. Because there are practical limits on how much patients and their insurance are willing to pay, the price of a drug cannot be increased to compensate for lack of sales when other drugs can be used as cheaper, but less effective substitutes. For this reason, the only way to make antibiotics profitable is to increase the number of units sold. However, increasing the number of units sold is frustrated because of limited patent terms in addition to conservative prescribing practices. Ultra-long patent terms may provide the key for making antibiotic development profitable, and thus help curb antibiotic resistance.

Patent rights remain an excellent way to conserve antibiotic use and spur innovation. Private innovation is likely superior to an alternative of drug innovation at the hands of the federal government in both practicality and cost. To adequately compensate a pharmaceutical company committed to novel antibiotic development, the patent term should be adjusted to match a possible reward of research in other areas of medicine like oncology or cardiovascular health. The average blockbuster drug brings in 7.5 Billion dollars in sales, and to spur innovation in the field of antibiotics, a company should expect at least a chance of achieving blockbuster status prior to their initial investment. When considering the most profitable antibiotics to date, in light of current incentive structures offered by not pursuing antibiotic research, the patent term for a novel antibiotic should be increased to somewhere between 63.75 to 70 years to adequately compensate the patentee.

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1. Antibiotic, Merriam-Webster, https://www.merriam-webster.com/dictionary/antibiotic (last visited Nov. 2, 2019).

2. See How Antibiotic Resistance Happens, Ctrs. for Disease Control & Prevention, (Aug. 22, 2018), https://www.cdc.gov/drugresistance/about/how-resistance-happens.html.

3. About Antibiotic Resistance, Ctrs. for Disease Control & Prevention, (Sep. 10, 2018), https://www.cdc.gov/drugresistance/about.html.

4. Mohammed et al., Interagency Coordination Grp. on Antimicrobial Resistance, No Time to Wait: Securing the Future From Drug-Resistant Infections Report to the Secretary-General of The United Nations 1 (2019), https://www.who.int/docs/default-source/documents/no-time-to-wait-securing-the-future-from-drug-resistant-infections-en.pdf?sfvrsn=5b424d7_6.

5. Id. at 4.

6. See JM Conly & BL Johnston, Where Are All the New Antibiotics? The New Antibiotic Paradox, 16(3) Can. J. Infect. Dis. Med. Microbio. 159, 160 (2005); See Jorn Sonderholm, Wild-Card Patent Extensions as a Means to Incentivize Research and Development of Antibiotics, 37 J. Law. Med. & Ethics 240 (2009) (A patent term is the time for which an invention is protected by the patent, and others in the United States are excluded from making, using, selling, importing, or shipping the patented invention during that time frame).

7. Andy Brunning, A Brief Overview of Classes of Antibiotics, Compound Int. (Oct. 10, 2019, 10:04 AM), https://www.compoundchem.com/2014/09/08/antibiotics/.

8. Regina Bailey, Taxonomy and Organism Classification, ThoughtCo (Nov. 5, 2019), https://www.thoughtco.com/taxonomy-373415.

9. Id.

10. See Replication and Distribution of DNA during Mitosis, Nature (Nov. 2, 2019), https://www.nature.com/scitable/topicpage/replication-and-distribution-of-dna-during-mitosis-6524841/.

11. Id. (Binary fission creates an exact clone of the organism).

12. See generally Lisa Bartee et al., Principles of Biology 524-29, https://openoregon.pressbooks.pub/mhccmajorsbio/chapter/dna-replication-in-eukaryotes/.

13. See Kavita Naik, The Structure of the Eukaryotic Cell, Sciencing (June 25, 2019), https://sciencing.com/structure-eukaryotic-cell-5197013.html.

14. Id.

15. Id.

16. Nat’l Inst. of Gen. Med. Sci., Bleach vs. Bacteria: Development of New Drugs to Breach Microbial Defenses, Sci. Daily (Apr. 7, 2014), www.sciencedaily.com/releases/2014/04/140407090214.htm

17. Id.

18. Paul Solman, Why So Many Companies Have Stopped Trying to Create New Antibiotics, PBS News Hour (Aug. 3, 2017), https://www.pbs.org/newshour/economy/why-economics-cant-solve-the-antibiotics-crisis (statement of John Rex, former executive at AstraZeneca Pharmaceuticals,“It’s actually pretty easy to kill bacteria. Steam, fire, bleach — they all work great”).

19. Sean E. Rossiter et al., Natural Products as Platforms to Overcome Antibiotic Resistance, 117(19) CHEM REV. 2 (2017).

20. See William C. Shiel, Medical Definition of Antibiotic, MEDICINE.NET (Nov. 2. 2019), https://www.medicinenet.com/script/main/art.asp?articlekey=8121

21. See id.

22. Id.

23. Id.

24. Andy Brunning, A Brief Overview of Classes of Antibiotics, Compound Int. (Oct. 10, 2019, 10:04 AM), https://www.compoundchem.com/2014/09/08/antibiotics/.

25. Id.

26. Id.

27. Id.

28. See id.

29. Kathryn Senior, How Many Types of Bacteria Are There?, Types of Bacteria (Mar. 23, 2019), http://www.typesofbacteria.co.uk/how-many-types-bacteria-are-there.html (There are at least seven major categories of bacteria including gram-positive cocci, gram-negative cocci, gram positive-bacilli, gram-negative bacilli, spirochetes, rickettsia, and mycoplasma. According to the author, “[i]n 1998, an American microbiologist worked out that the number of bacteria on Earth at that time was five million trillion. This is the number 5 followed by thirty zeroes.”).

30. Sagar Aryal, Differences Between Gram Positive and Gram Negative Bacteria, Microbiology info. (Aug. 15, 2019), https://microbiologyinfo.com/differences-between-gram-positive-and-gram-negative-bacteria/.

31. Id.

32. Id.

33. Id.

34. Mohammed et al., supra note 4, at 1.

35. See About Antimicrobial Resistance, Ctrs. for Disease Control & Prevention (Sept. 10, 2018), https://www.cdc.gov/drugresistance/about.html.

36. Id.

37. But see Cornell Dep. of Microbiology, Binary Fission and Other Forms of Reproduction in Bacteria, Dep’t of Microbiology, Cornell Cals (Nov. 2, 2019, 6:50 PM), https://micro.cornell.edu/research/epulopiscium/binary-fission-and-other-forms-reproduction-bacteria/ (differentiating E. Coli from stanieria because stanieria does not undergo binary fission.“[Stanieria] starts out as a small, spherical cell approximately 1 to 2 µm in diameter. This cell is referred to as a baeocyte (which literally means “small cell.” The baeocyte begins to grow, eventually forming a vegetative cell up to 30 µm in diameter. As it grows, the cellular DNA is replicated over and over, and the cell produces a thick extracellular matrix. The vegetative cell eventually transitions into a reproductive phase where it undergoes a rapid succession of cytoplasmic fissions to produce dozens or even hundreds of baeocytes. The extracellular matrix eventually tears open, releasing the baeocytes.”).

38. See Kenneth Todar, The Growth of Bacterial Populations, Todar’s Online Textbook of Bacteriology (Nov. 2, 2019, 7:00 PM), http://textbookofbacteriology.net/growth_3.html (noting there are additional phases of bacterial growth besides just exponential growth, including lag phase, stationary phase, and death phase).

39. Bacteria, Microbio. Soc’y, (Nov. 2, 2019, 6:50 PM), https://microbiologyonline.org/about-microbiology/introducing-microbes/bacteria.

40. See generally David Spiegelhalter & Owen Smith, Understanding Uncertainty: Infinite Monkey Business, Plus Mag. (Mar. 1, 2010), https://plus.maths.org/content/infinite-monkey-business (The infinite monkey theorem states that a monkey typing on a typewriter, given infinite time, will eventually type out a transcript of one of William Shakespeare’s plays. The Authors go through great lengths to mathematically explore the possibilities of infinity. In the context of antibiotic resistance, the analogy is especially relevant. Given the right conditions and enough time, eventually through random mutation, a bacterium will develop a genetic mechanism to overcome a particular means of antibiotic susceptibility.).

41. See generally Bacterial Transformation, Sci. Learning Hub (Nov. 16, 2007), https://www.sciencelearn.org.nz/resources/2032-bacterial-transformation.

42. See generally Transfection, New World Encyclopedia (Feb. 22, 2009), https://www.newworldencyclopedia.org/entry/Transfection.

43. Sci. Learning Hub, supra note 41.

44. See generally Eric Kades, Preserving a Precious Resource: Rationalizing the Use of Antibiotics, 99 Nw. U. L. Rev. 611, 619 (2005) (citing Stuart B. Levy, Antibiotic Resistance: An Ecological Imbalance, 5 Antibiotic Resistance: Origin, Evolution, Selection and Spread (1997)).

45. See L. Anderson, Why Don’t Antibiotics Kill Viruses, Drugs.com (last updated Jun. 21, 2019), https://www.drugs.com/article/antibiotics-and-viruses.html.

46. Id.

47. A simple way to conceptualize a virus is to imagine it as a hypodermic syringe, filled with viral genetic information. The syringe is representative of the virus’ protein coat, and the genetic information is what is housed in a virus structure. The virus floats along until it encounters a host cell. The virus protein coat will attach to the host cell’s surface, and just like a shot, the viral genetic information will be injected into the host. The viral genetic material is indistinguishable from that of the host, and via complex molecular pathways, the host cell replicates and translates the viral information. The host creates more viral genetic material and protein coats. Eventually, the hijacked cell dies, and in the process, releases the newly minted viruses.

48. See generally Luis P. Villarreal, Are Viruses Alive?, Scientific Am. (Dec. 2004), https://www.scientificamerican.com/article/are-viruses-alive-2004/

49. L. Anderson, supra note 45.

50. Eric Kades, Preserving a Precious Resource: Rationalizing the Use of Antibiotics, 99 Nw. U. L. Rev. 611, 626 (2005) (The author provides an excellent example illustrating a hypothetical physician’s thought process when deciding to prescribe an antibiotic. “A patient goes to the doctor with ear pain. Based on an initial examination, the doctor concludes that the patient has an infection, and that there is a 75% chance that it is viral, and only a 25% chance that it is bacterial. In either case, the infection is not serious; the patient is likely to experience two to three days of moderate discomfort and then recover. A culture test, to determine whether the infection is bacterial or viral, takes a couple days and costs more than an antibiotic prescription. Weighing the modest cost of the drugs against a couple days of discomfort, the patient is willing to pay for the antibiotics even though she realizes that there is only a twenty-five percent chance that they will provide any relief. Under these facts, the patient will press her doctor for the prescription and likely obtain it: making patients happy is good for business, and the specter of a malpractice suit if the infection turns out to be bacterial and serious provides further impetus to write the prescription.”).

51. Pew Charitable Trusts, Trends in U.S. Antibiotic Use, 2018 Despite Some Progress in Data Collection and Availability, More Information is Needed to Improve Prescribing, Combat the Threat of Resistant Bacteria, Pew (Aug. 1, 2018), https://www.pewtrusts.org/en/research-and-analysis/issue-briefs/2018/08/trends-in-us-antibiotic-use-2018 (citing Katherine E. Fleming-Dutra et al., Prevalence of Inappropriate Antibiotic Prescriptions Among US Ambulatory Care Visits, 2010-2011, 315(17) J. Am. Med. Ass’n, 1864–73 (2016)).

52. Chris Dall, FDA Plan Focuses on Antibiotic Development, Stewardship, CidRap (Sep. 14, 2018), http://www.cidrap.umn.edu/news-perspective/2018/09/fda-plan-focuses-antibiotic-development-stewardship (The FDA “has made strides in this area through the implementation of two Guidances for Industry (GFI #209 and GFI #213), which seek to end the use of medically important antibiotics for growth promotion in food-producing animals and brought 95% of medically important antibiotic used in food-animal water and feed under veterinary supervision.”).

53. Gary L. Cromwell, How and Why Antibiotics Are Used in Swine Production, 13 Animal Biotech. 7–10 (2002) (The author lists the various antibiotics used in swine production in table 1 on page 9, and table 11 on page 16. Use of many of the antibiotics listed are either have been or are scheduled to be discontinued).

54. See Sung-Eun Cho, Growth Promoting Antibiotics for Animals, MicrobeWiki (last edited Dec. 12, 2012, 7:57 PM), https://microbewiki.kenyon.edu/index.php/Growth_promoting_antibiotics_for_animals (The author describes the process where low levels of antibiotics prevent the animal from expending energy to develop its own immune system for its gut flora. With this savings in energy, the animal is able to grow larger).

55. Anne Gulland, Countries Still Using Antibiotics to Fatten Animals Despite Ban, Telegraph (Feb. 14, 2019, 12:01 AM), https://www.telegraph.co.uk/global-health/science-and-disease/countries-still-using-antibiotics-fatten-animals-despite-ban/.

56. Chris Dall, supra note 52.

57. Id.

58. Anne Gulland, supra note 55.

59. Id.

60. Vabomere (Meropenem and Vaborbactam), CenterWatch (Nov. 4, 2019, 11:47 AM), https://www.centerwatch.com/drug-information/fda-approved-drugs/drug/100222/vabomere-meropenem-and-vaborbactam. (All information contained in row 1 of Table 2 spanning Drug to Manufacturer including terms in direct quotations can be found at the source delineated in this citation).

61. Yuman Lee et al., Meropenem–Vaborbactam (Vabomere™): Another Option for Carbapenem-Resistant Enterobacteriaceae, 44(3) Pharmacy & Therapeutics 110, 111 (2019) (“Resistance to Meropenem was reported in only three patients with Klebsiella pneumoniae (3.3% of the microbiologic modified ITT group vs. 7.4% of the microbiologic evaluable group)”).

62. Baxdela (Delafloxacin) Tablets and Injection, CenterWatch (Nov. 4, 2019, 12:18 PM), https://www.centerwatch.com/drug-information/fda-approved-drugs/drug/100207/baxdela-delafloxacin-tablets-and-injection (All information contained in row 2 of Table 2 spanning Drug to Manufacturer including terms in direct quotations can be found at the source delineated in this citation).

63. Sarah C. J. Jorgensen et al., Delafloxacin: Place in Therapy and Review of Microbiologic, Clinical and Pharmacologic Properties, 7(2) Infectious Diseases & Therapy 197, 208 (2018) (Resistance to Delafloxacin (Baxdela) was very small and only found in vitro amongst strains with a prior QRDR mutation).

64. Lesley J. Scott, Eravacycline: A Review in Complicated Intra-Abdominal Infections, 79(3) Drugs 315 (2019) (All information contained in row 3 of table 2 spanning Drug to Manufacturer including terms in direct quotations can be found at the source delineated in this citation).

65. Id. at 318 (“Eravacycline [Xerava] resistance in some bacteria is associated with up-regulation of non-specific intrinsic MDR efflux and target-site modifications such as to the 16S RNA or certain 30S ribosomal proteins (e.g. S10). Resistance to Eravacycline has also been observed in Enterococcus spp. isolates harboring mutations encoded by rpsJ”) (citing Tetraphase Pharmaceuticals Inc., Xerava (Eravacycline): US Prescribing Information, Fda (Oct. 21, 2018), https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf; Xerava (Eravacycline): Summary of Product Characteristics, Eur. Med. Agency (Nov. 1, 2018), http://www.ema.europa.eu/.).

66. James A. Karlowsky, et al., Microbiology and Preclinical Review of Omadacycline, 69 (Supp 1) Clinical Infectious Diseases S6-S15 (2019) (all information contained in row 4 of Table 2 spanning Drug to Manufacturer including terms in direct quotations can be found at the source delineated in this citation.).

67. Id at S6 (“To date, the resistance mechanisms that have been found to inhibit the activity of omadacycline include multidrug efflux pumps (MexXY-OprM and MexAB-OprM) and the tetracycline monooxygenase TetX (Paratek Pharmaceuticals, Inc.; data on file). Although TetX has been shown to inactivate all known tetracyclines, it is not a widespread resistance determinant.” (citing A. Ruzin et al., Studies on the Mechanism of Resistance to PTK796 in Psudomonas aeruginosa and Klebsiella pneumoniae, ICAAC (2010), https://paratekpharma.com/media/1157/ruzin2010icaacmechanism-of-resistance.pdf)).

68. Bülent Bozdogan & Peter C. Appelbaum, Oxazolidinones: Activity, Mode of Action, and Mechanism of Resistance, 23 Int’l J. of Antimicrobial Agents 113, 116 (2004) (“Oxazolidinone resistant strains generated in the laboratory, have been reported. Decreased affinity of ribosome for the oxazolidinones due to mutations at 23S rRNA is the cause of resistance to these drugs.”); Mekki Bensaci & Daniel Sahm, Surveillance of Tedizolid Activity and Resistance: In Vitro Susceptibility of Gram-Positive Pathogens Collected over 5 Years from the United States and Europe, 87 Diagnostic Microbiology & Infectious Disease 133, 138 (2017) (“Overall, 99.7% of the tested organisms (11,196 of 11,231) were susceptible to tedizolid at an MIC 0.5 mg/L or lower.”).

69. Maria Sorbera et al., Ceftolozane/Tazobactam: A New Option in the Treatment of Complicated Gram-Negative Infections, 39 Pharmacy & Therapeutics 825, 825, 831 (2014) (all information contained in row 6 of Table 2 spanning Drug to Manufacturer including terms in direct quotations can be found at the source delineated in this citation).

70. Jordan R. Smith et al., Dalbavancin: A Novel Lipoglycopeptide Antibiotic with Extended Activity Against Gram-Positive Infections, 4 Infectious Diseases & Therapy 245, 246-47 (2015) (all information contained in row 7 of Table 2 spanning Drug to Manufacturer including terms in direct quotations can be found at the source delineated in this citation).

71. Id. at 248 (“Only three staphylococcal isolates (0.3%) and 14 streptococcal isolates (4%) possessed dalbavancin [Dalvance] MIC values above the currently proposed FDA breakpoint. Each resistant streptococcal isolate was a member of the species S. agalactiae.”).

72. Samantha Rosenthal et al., Oritavancin (Orbactiv) A New-Generation Lipoglycopeptide for the Treatment Of Acute Bacterial Skin and Skin Structure Infections, 43 Pharmacy & Therapeutics 143, 143-44 (2018) (all information contained in row 8 of Table 2 spanning Drug to Manufacturer including terms in direct quotations can be found at the source delineated in this citation).

73. Ronald N. Jones et al., Results from Oritavancin Resistance Surveillance Programs (2011 to 2014): Clarification for Using Vancomycin as a Surrogate to Infer Oritavancin Susceptibility, 60 Antimicrobial Agents & Chemotherapy 3174, 3175 (2016) (“Among 215 retested isolates of S. aureus, only 1.4% (3 isolates) had reproducible oritavancin MIC results of ≥0.25 ug/ml. Similarly, repeated β-hemolytic streptococcal reproducibility ranged from nil (Streptococcus pyogenes) to 6.7% (Streptococcus agalactiae). The most frequently reproducible oritavancin-nonsusceptible results were recorded for Streptococcus dysgalactiae (MIC of 0.5 ug/ml, 1 doubling dilution above the breakpoint). ”).

74. Ryan K. Shields et al., Emergence of Ceftazidime-Avibactam Resistance Due to Plasmid-Borne blaKPC-3 Mutations During Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections, 61 Antimicrobial Agents & Chemotherapy 1 (2017) (all information contained in row 9 of Table 2 spanning Drug to Manufacturer including terms in direct quotations can be found at the source delineated in this citation).

75. Id. at 1 (“Ceftazidime-avibactam-resistant K. pneumoniae emerged in three patients after ceftazidime-avibactam treatment for 10 to 19 days.”).

76. Zemdri (Plazomicin), CenterWatch (Nov. 8, 2019, 1:25 PM), https://www.centerwatch.com/drug-information/fda-approved-drugs/drug/100308/zemdri-plazomicin (all information contained in row 10 of Table 2 spanning Drug to Manufacturer including terms in direct quotations can be found at the source delineated in this citation).

77. Anne Witzky et al., Translational Control of Antibiotic Resistance, 9 Open Bio. 1, 6 (2019) (“However, plazomicin was not effective in vitro against strains expressing 16 S methylase armA, indicating that it is not immune to all modes of aminoglycoside resistance.” (citing James B. Aggen et al., Synthesis and Spectrum of the Neoglycosien ACHN-490, 54 Antimicrobial Agents & Chemotherapy 4636 (2010))).

78. Recarbrio (Imipenem, Cilastatin, and Relebactam), CenterWatch (July 23, 2019), https://www.centerwatch.com/directories/1067-fda-approved-drugs/listing/4098-recarbrio-imipenem-cilastatin-and-relebactam (all information contained in row 11 of Table 2 spanning Drug to Manufacturer including terms in direct quotations can be found at the source delineated in this citation).

79. Robert P. Gaynes & David H. Culver, Resistance to Imipenem Among Selected Gram-Negative Bacilli in the United States, 13 Infection Control & Hosp. Epidemiology 10, 10 (1992) (“For P aeruginosa, 11.1% of the isolates were resistant to imipenem; 16.1% were either intermediate-susceptible or resistant to the drug. A logistic regression model found that resistance was more common among P aeruginosa isolated from the respiratory tract, patients in intensive care units, and in teaching hospitals. Additionally, resistance to imipenem increased by 25% in teaching hospitals from 1986-1988 to 1989-1990.”).

80. Pretomanid Tablets, CenterWatch (Jan. 20, 2020, 5:08 PM), https://www.centerwatch.com/directories/1067-fda-approved-drugs/listing/4033-pretomanid-tablets (all information contained in row 12 of Table 2 spanning Drug to Manufacturer including terms in direct quotations can be found at the source delineated in this citation).

81. Id. (“Treatment failure was defined as the incidence of bacteriologic failure (reinfection – culture conversion to positive status with different M. tuberculosis strain), bacteriological relapse (culture conversion to positive status with same M. tuberculosis strain), or clinical failure through follow-up until 6 months after the end of treatment. Of the 107 patients assessed, outcomes were classified as success for 95 (89%) patients and failure for 12 (11%) patients.”).

82. Xenleta (lefamulin), CenterWatch (Aug. 21, 2019), https://www.centerwatch.com/directories/1067-fda-approved-drugs/listing/4456-xenleta-lefamulin (all information contained in row 13 of Table 2 spanning Drug to Manufacturer including terms in direct quotations can be found at the source delineated in this citation).

83. Rodrigo E. Mendes et al., In Vitro Activity of Lefamulin Tested Against Streptococcus Pneumoniae with Defined Serotypes, Including Multidrug-Resistant Isolates Causing Lower Respiratory Tract Infections in the United States, 60 Antimicrobial Agents & Chemotherapy 4407, 4408 (2016) (look to Table 1, at a concentration of 1µg/ml Lefamulin (Xenleta) was 99.9% effective against all strains tested).

84. Fetroja (Cefiderocol), CenterWatch (Nov. 19, 2019, 1:25 PM), https://www.centerwatch.com/directories/1067-fda-approved-drugs/listing/4557-fetroja-cefiderocol (all information contained row in 14 of Table 2 spanning Drug to Manufacturer including terms in direct quotations can be found at the source delineated in this citation).

85. Yoshinori Yamano, In Vitro Activity of Cefiderocol Against a Broad Range of Clinically Important Gram-negative Bacteria, 69 Clinical Infectious Diseases S544, S547 (2019) (Table 2 in Yamaro’s paper shows partial resistance to Cefiderocol (Fetroja), despite overall effectiveness (citing Meredith A. Hackel et al., In vitro Activity of the Siderophore Cephalosporin, Cefiderocol, Cgainst Carbapenem- Nonsusceptible and Multidrug-Resistant Isolates of Gram-Negative Bacilli Collected Worldwide in 2014 to 2016, 62 Antimicrobial Agents & Chemotherapy 1, 1-13 (2018))).

86. Sanjay Sethi, Community-Acquired Pneumonia, Merkmanuals.com (Dec. 2020), https://www.merckmanuals.com/professional/pulmonary-disorders/pneumonia/community-acquired-pneumonia.

87. Mark Terry, First Antibiotic with New Mechanism of Action Approved in Almost 20 Years, BioSpace (Aug. 20, 2019), https://www.biospace.com/article/fda-approves-nabriva-s-xenleta-for-bacterial-pneumonia/.

88. J. Stewart, Fetroja Approval History, Drugs.com (Nov. 19, 2019), https://www.drugs.com/history/fetroja.html.

89. Meeting the Demand for New Antibiotics, Nabriva.com, https://www.nabriva.com/therapeutics (last visited Aug. 25, 2021).

90. Antibiotics Market Size Worth $62.06 Billion By 2026 | CAGR: 4.0%, Grand View Research (Feb. 2019), https://www.grandviewresearch.com/press-release/global-antibiotic-market (“The global antibiotics market size is expected to reach USD 62.06 billion by 2026 expanding at a CAGR of 4.0%, according to a new report by Grand View Research, Inc.”).

91. The Hatch-Waxman Act: A Primer, EveryCRSReport (Sept. 28, 2016), https://www.everycrsreport.com/reports/R44643.html#_Toc463343283.

92. Id.

93. Id.

94. Id.

95. Kurt R. Karst, New Life for Old Antibiotics – Senate Passes Bill Creating New Exclusivity Provisions; House Passage is Expected Very Soon, FDA L. Blog (Sept. 26, 2008), http://www.fdalawblog.net/2008/09/new-life-for-ol/.

96. Id.

97. Id.

98. See generally William C. Shiel, Medical Definition of Antibiotic, medicinenet (Nov. 2, 2019), https://www.medicinenet.com/script/main/art.asp?articlekey=8121.

99. Ursula Theuretzbacher et al., Reviving Old Antibiotics, 70 J. Antimicrobial Chemotherapy 2177, 2179 (2015) (citing Johan W. Moutonet al., Conserving Antibiotics for the Future: New Ways to Use Old and New Drugs from a Pharmacodynamic Perspective, 14 Drug Resist Update 107, 107-17 (2011)).

100. Dep’t of Health and Human Servs., Generating Antibiotic Incentives 1, 5, https://www.fda.gov/media/110982/download (2019).

101. Id. at 6.

102. Zachary Brennan, Updated: FDA to Congress: Consider Changes to GAIN Act, Regul. Affs. Pros. Soc’y (Feb. 08, 2018), https://www.raps.org/news-and-articles/news-articles/2018/2/fda-to-congress-consider-changes-to-gain-act (“Aaron Kesselheim, associate professor of medicine at Harvard Medical School and a faculty member in the Division of Pharmacoepidemiology and Pharmacoeconomics in the Department of Medicine at Brigham and Women’s Hospital, [stated] … ‘Now almost 6 years later, I don’t see any evidence that the GAIN Act has led to any change at all in the antibiotic pipeline. It’s not surprising, of course, since the main thing GAIN did was increase the minimum generic-free market exclusivity period from about 5-7 years to 10-12 years, and most new antibiotics already have at least that much time remaining on their patents … I don’t think tweaks to the law would make it any more effective. However, if the FDA report is emphasizing that legislative drug development incentives should be designed to go to maximally innovative and clinically effective drugs rather than just any drug in which the manufacturer makes an incremental change, that’s a sensible recommendation.’”).

103. Dep’t of Health and Human Servs., supra note 103 at 10-11, tbl.2 (Footnote 13 on that page states “The following types of exclusivity may be extended by GAIN exclusivity: New Chemical Entity Exclusivity (5 years) described in sections 505(c)(3)(E)(ii) and 505(j)(5)(F)(ii) of the FD&C Act, New Clinical Investigation Exclusivity (3years) described in sections 505(c)(3)(E)(iii) and (iv) and 505(j)(5)(F)(iii) and (iv) of the FD&C Act, and Orphan Drug Exclusivity (7 years) described in section 527 of the FD&C Act. Any GAIN exclusivity extension is in addition to any extension period under section 505A of the FD&C Act with respect to the drug.”).

104. See Michael Gabay, RxLegal 21st Century Cures Act, 52 Hosp. Pharmacy 264, 265 (2017).

105. Interoperability refers to the ability to transfer patient medical records between healthcare providers with ease.

106. 21st Century Cures Act, Pub. L. No. 114-255, § 3001, 130 Stat. 1033 (2016).

107. Id.

108. Id.

109. Id.

110. Tom Frieden, Why the ‘Gold Standard’ of Medical Research is No Longer Enough, statnews (Aug. 2, 2017), https://www.statnews.com/2017/08/02/randomized-controlled-trials-medical-research/.

111. Gabay, supra note 107, at 264 (“The language within the Act states that the Secretary of Health and Human Services ‘shall determine whether to accept a qualification submission based on factors which may [emphasis added] include the scientific merit’ of the submission. Although this language may expedite the FDA approval process, some clinicians worry that this approach could result in approvals based upon lower quality data.”).

112. Frieden, supra note 113.

113. Id.

114. 21st Century Cures Act, Pub. L. No. 114-255, §3022, 130 Stat. 1033 (2016).

115. Id.

116. Antimicrobial Resistance Information from FDA, u.s food & drug admin., https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/antimicrobial-resistance-information-fda (last visited Dec. 20, 2019).

117. Federal Food, Drug, and Cosmetics Act, 21 U.S.C. § 356 (h) (2016).

118. See infra Table 2.

119. u.s food & drug admin., supra note 119.

120. Id.

121. Federal Food, Drug, & Cosmetic Act, 21 U.S.C. § 505(j)(5)(B)(iv)(II)(bb) (1984).

122. Jon Hess & Shannon Litalien, Battle for the Market: Branded Drug Companies’ Secret Weapons Generic Drug Makers Must Know, 3 J. Generic Meds. 20, 26 (2005).

123. Part II: New Trends Reshaping Healthcare M&A – Intellectual Property (IP), Wolters Kluwer (Jan. 08, 2016), https://www.wolterskluwer.com/en/expert-insights/intellectual-property-ip-trends-reshaping-healthcare-m-and-a.

124. Matthew Harper, The Cost of Developing Drugs Is Insane. That Paper That Says Otherwise Is Insanely Bad, Forbes (Oct. 16, 2017), https://www.forbes.com/sites/matthewherper/2017/10/16/the-cost-of-developing-drugs-is-insane-a-paper-that-argued-otherwise-was-insanely-bad/#b442c382d459.

125. Matt Kuhrt, Prices for Top-Selling Drugs Appear Immune to Common Market Forces: Study, Fierce Healthcare (June 3, 2019, 7:30 AM), https://www.fiercehealthcare.com/hospitals-health-systems/prices-for-top-selling-drugs-continue-to-rise-unchecked.

126. Counting the Cost of Failure in Drug Development, Pharm. Tech., https://www.pharmaceutical-technology.com/features/featurecounting-the-cost-of-failure-in-drug-development-5813046/ (last updated Jan. 27, 2020, 5:14 AM).

127. See generally Antibiotics and the Breakdown in the Patient-Doctor Relationship, utswmed, https://utswmed.org/medblog/antibiotics-evidence-based-medicine/ (last visited Aug. 21, 2017).

128. How Do Antibiotics Work?, healthline (May 4, 2018), https://www.healthline.com/health/how-do-antibiotics-work.

129. JM Conly & BL Johnston, Where Are All the New Antibiotics? The New Antibiotic Paradox, Can. J. Infectious Diseases & Med. Microbio. 159 (2005).

130. Jessica P. Schulman, Patents and Public Health: The Problems with Using Patent Law Proposals to Combat Antibiotic Resistance, 59 DePaul L. Rev. 221, 235-36 (2009) (citing Kevin Outterson, The Vanishing Public Domain: Antibiotic Resistance, Pharmaceutical Innovation, and Intellectual Property Law, 67 Pitt. L. Rev. 67, 93, 100 (2005)).

131. Id. at 255.

132. Our Mission, TB-Alliance (Jan. 4, 2020, 3:38 PM), https://www.tballiance.org/about/mission.

133. Dania Nadeem, Antibiotics Maker Melinta Files for Chapter 11 Bankruptcy, reuters (Dec. 27, 2019, 9:59 AM), https://www.reuters.com/article/us-melinta-bankruptcy/antibiotics-maker-melinta-files-for-chapter-11-bankruptcy-idUSKBN1YV1AT.

134. TTPH Tetraphase Pharmaceuticals, Inc. Common Stock, Nasdaq (Jan. 6, 2020, 10:40 AM), https://www.nasdaq.com/market-activity/stocks/ttph (closed on 7/20/15 at $1025.40 per share, 1/2/20 at $2.93 per share).

135. PRTK Paratek Pharmaceuticals, Inc. Common Stock, Nasdaq (Jan. 6, 2020, 10:45 AM), https://www.nasdaq.com/market-activity/stocks/prtk (closed on 7/20/15 at $25.86 per share, 1/2/20 at $3.99 per share).

136. See Damian Garde, Merck Dumps 120 Cubist Researchers After its $9.5B Merger, Fierce Biotech (Mar. 5, 2015, 4:33 PM), https://www.fiercebiotech.com/r-d/merck-dumps-120-cubist-researchers-after-its-9-5b-merger.

137. Sarah Toy, Allergan Acquisition Is ‘a Major Bailout’ for Shareholders According to Analysts, MarketWatch (June 26, 2019, 7:37 AM), https://www.marketwatch.com/story/allergan-acquisition-is-a-major-bailout-for-shareholders-according-to-analysts-2019-06-25.

138. Andrew Dunn, Achaogen Files for Bankruptcy Protection, Seeks Asset Sale, BioPharma Dive (Apr. 15, 2019), https://www.biopharmadive.com/news/achaogen-files-for-bankruptcy-protection-seeks-asset-sale/552737/.

139. NBRV Nabriva Therapeutics plc Ordinary Shares Ireland, Nasdaq (Jan. 6, 2020, 11:53 AM), https://www.nasdaq.com/market-activity/stocks/nbrv (closed on 7/20/15 at $10.81 per share, 1/2/20 at $1.32 per share).

140. See Trump Says ‘This Is the Greatest Economy in the HISTORY of America.’ No, Eisenhower’s Probably Was, Fortune (June 7, 2018), https://fortune.com/2018/06/07/trump-eisenhower-greatest-economy-history-america/.

141. If they were economically sound, you would not need the government paying you to do them.

142. Robert Kiyosaki, Rich Dad Poor Dad Scam #6: Your House is an Asset, Rich dad (Dec. 24, 2019), https://www.richdad.com/is-house-an-asset. (“In reality, an asset is only something that puts money in your pocket. So-called financial experts have lots of fancy accounting maneuvers to make things that aren’t assets look like assets, and they can be helpful for certain situations. But in the real world where you need money in your pocket to survive, if you have a house, paid for or not, that you live in, then it really isn’t an asset. Instead of putting money in your pocket, it takes money out of your pocket in the form of a mortgage, utility payments, taxes, maintenance, and more. That is the simple definition of a liability.”).

143. Tim Parker, The Cost of Raising a Child in America, investopedia (May 20, 2019), https://www.investopedia.com/articles/personal-finance/090415/cost-raising-child-america.asp. (“In total, once a child reaches adulthood (age 18), parents will have spent an average of $284,570… Nobody wants to think of their children as just an expense, but at an average annual cost of almost $17,000 (and the possibility that it could be higher, thanks to where you live and childcare), the financial side of child-rearing can’t be ignored.”).

144. Tokenism, merriam-webster, https://www.merriam-webster.com/dictionary/tokenism (last visited Jan. 4, 2020, 8:30 PM). (“Definition of tokenism: the policy or practice of making only a symbolic effort (as to desegregate)”).

145. Eric Kades, Preserving a Precious Resource: Rationalizing the Use of Antibiotics, 99 Nw. U. L. Rev. 611, 638 (2005).

146. Id.

147. Jessica P. Schulman, Patents and Public Health: The Problems with Using Patent Law Proposals to Combat Antibiotic Resistance, 59 DePaul L. Rev. 221, 238 (2009).

148. Id. at 239.

149. Id. at 240.

150. Quora, Antibiotics Are Money-Losers for Big Pharma. How Can We Incentivize the Development of New Ones?, Forbes (Jan. 2, 2018, 11:20 AM), https://www.forbes.com/sites/quora/2018/01/02/antibiotics-are-money-losers-for-big-pharma-how-can-we-incentivize-the-development-of-new-ones/#42254310487f.

151. Why Bacteria is Resistant to Penicillin?, AssignmentExpert, https://www.assignmentexpert.com/blog/why-bacteria-are-resistant-to-penicillin/. (last visited Nov. 14, 2020).

152. Quora, supra note 150.

153. Jorn Solderholm, Wild-Card Patent Extensions as a Means to Incentivize Research and Development of Antibiotics, J. Law. Med. & Ethics 240, 241 (2009).

154. Id.

155. Id. at 243.

156. Cf. Eric Kades, Preserving a Precious Resource: Rationalizing the Use of Antibiotics, 99 Nw. U. L. Rev. 611, 655 (2005) (Kades discusses at length extending a patent term so that a company “acting in self-interest, [can] preserve the effectiveness of antibiotics in anticipation of a plague.” Kades argues that a monopolist is able to make maximum profits when demand for the monopolized product is at its height, as in during a plague. Contrary to Kades, the present author argues that patent terms should be extended to a point that makes antibiotic development equally attractive to a pharmaceutical company, and the author subsequently calculates what that time extension should be).

157. See Jessica P. Schulman, Patents and Public Health: The Problems with Using Patent Law Proposals to Combat Antibiotic Resistance, 59 DePaul L. Rev. 221, 240 (2009).

158. Cf. Xueni Pan et al., The Responses of Medical General Practitioners to Unreasonable Patient Demand for Antibiotics - A Study of Medical Ethics Using Immersive Virtual Reality, PLoS ONE 1, 2 (2016) (“In prescriptions for children, Mangione-Smith et al. found that perceived parental expectations played a major role in the prescription of antibiotics for viral infections, and a later study found that parental misconceptions about the utility of antibiotics was a prevalent factor, especially amongst parents relying on Medicaid in the United States, as reported by Kleinman et al.”) (Citing Mangione-Smith R et al., The Relationship Between Perceived Parental Expectations and Pediatrician Antimicrobial Prescribing Behavior, 103(4) Pediatrics 711, 718; Vaz LE & Kleinman KP, Misconceptions About Antibiotic Use, Pediatrics 0883 (2015)).

159. Meir P. Pugatch, The International Political Economy of Intellectual Property Rights 29 (Edward Elgar Pub. Ltd. ed., MPG Books Ltd. 2004) (citing Nogues 1990a:7; Nordhaus 1969 52, fn 18.).

160. Id. (“it is not possible to have one optimal patent term for all inventions, any decision on a given term of protection, such as the current period of 20 years as stated in the TRIPS Agreement, must be arbitrary.”)

161. Gene Quinn, It’s Time to Talk About Longer Patent Term in America, IP Watchdog (Aug 30, 2017), https://www.ipwatchdog.com/2017/08/30/longer-patent-term-america/id=86190/ (“The brief duration of the patent term is why a patent is considered a wasting asset. Today, given the erosion of the patent rights over the last 12 years, one has to wonder whether the brief patent term is long enough to properly incentivize innovators.”).

162. U.S. Const. art. I, § 8, cl. 8 (“[The Congress shall have power] to promote the progress of science and useful arts, by securing for limited times to authors and inventors the exclusive right to their respective writings and discoveries.”).

163. A Brief History of the Patent Law of the United States, Ladas & Parry LLP: Edu. Ctr. (May 7, 2014), https://ladas.com/education-center/a-brief-history-of-the-patent-law-of-the-united-states-2/ (citing § 1 of the French patent law of 1791).

164. Manual of Patent Examining Procedures, Distinction Between Design and Utility Patents § 1502.01 (a) (2020).

165. See generally Arkie Lures, Inc. v. Gene Larew Tackle, Inc., 912 F. Supp. 422 (W.D. Ark. 1996) (This case involved obviousness regarding a salty tasting rubber lure used to catch bass.).

166. See generally Karl Aiginger & Michael Pfaffermayr, Looking at the Cost Side of “Monopoly”, 45 J. of Indus. Econ. 245, 263 (1997) (providing more information about deadweight loss and the economic implications of monopoly. The authors conclude that oligopoly and “cost inefficiency” contribute to dead weight loss.).

167. A drone sold for $1,000 multiplied by 2000 would cost 2 million dollars. Even if a team of programmers were paid a million dollars to develop the spotting software, once the marble is found, the prospector would still make a nine hundred-ninety-seven-million-dollar profit to share with their investors.

168. Quora, Antibiotics are Money-Losers For Big Pharma. How Can We Incentivize the Development of New Ones?, Forbes (Jan. 2, 2018, 11:20 AM), https://www.forbes.com/sites/quora/2018/01/02/antibiotics-are-money-losers-for-big-pharma-how-can-we-incentivize-the-development-of-new-ones/#42254310487f.

169. Id.

170. Id.

171. JM Conly & BL Johnston, Where Are All the New Antibiotics? The New Antibiotic Paradox, 16 Can. J. Infect. Dis. Med. Microbio. 159, 160 (2005).

172. Azithromycin: A World Best -Selling Antibiotic, wipo (July 11, 2012), https://www.wipo.int/ipadvantage/en/details.jsp?id=906.

173. Patent Term Calculator, uspto (Feb. 9, 2018), https://www.uspto.gov/patent/laws-and-regulations/patent-term-calculator (“In 1994 the US signed the Uruguay Round Agreements Act changed the date from which the term was measured. Because the term was measured from the filing date of the application and not the grant date of the patent, Congress amended 35 U.S.C. § 154 to provide for applications filed after June 7, 1995 that the term of a patent begins on the date that the patent issues and ends on the date that is twenty years from the date on which the application was filed in the U.S. or, if, the application contained a specific reference to an earlier filed application or applications under 35 USC 120, 121 or 365(c), twenty years from the filing date of the earliest of such application. In addition, 35 U.S.C. 154 was amended to provide term extension if the original patent was delayed due to secrecy orders, interferences, or appellate review periods.”).

174. 35. U.S.C. § 271(a) et seq

175. See us debt clock (Feb. 13, 2020 12:18 PM), https://www.usdebtclock.org/.

176. C.f. Jessica P. Schulman, Patents and Public Health: the Problems with Using Patent Law Proposals to Combat Antibiotic Resistance, 59 DePaul L. Rev. 221, 254 (2009).