Tag: biopharmaceutical

Categories
Biotech Patents Pharma

Reply and Response to C-IP2’s March 4, 2021, Blogpost on UC Hastings’ Evergreen Drug Patent Search Database

C-IP2’s original post on the UC Hastings’ Evergreen Drug Patent Search Database can be read here.

Reply to Blog Post on UC Hastings’ Evergreen Drug Patent Search Database

Robin Feldman
Arthur J. Goldberg Distinguished Professor of Law
Albert Abramson ’54 Distinguished Professor of Law Chair
Director of the Center for Innovation at University of California Hastings

We would like to thank the author of the blog post for taking the time to look at our work for the Evergreen Drug Patent Database. It is always appreciated when others explore and examine our data. In addition, the benefit of a website is that helpful feedback from visitors can be used to make the information more accessible and easier to navigate.

We would also like to point out that the blog post misunderstands the nature of the project. The project begins with the initial patent protection on the chemical formulation of a drug and then tracks additional protections. Some of these protections increase the amount of time that the drug is protected. Others increase the number of protections that a challenger would have to overcome, without extending the length of time.

One can think of the difference in terms of building a wall of protection. Some protections make the wall higher by extending the total time period. Other protections make the wall thicker, so it is tougher for a competitor to break through.

We do have a separate tab that allows one to calculate only the months of added protection, for those who wish to view the data in that manner. We also offer tabs to view the number of unique patents and the number of patent extensions. Our goal is to allow the user to examine the information through different lenses, so that one can understand the many ways a patent holder can extend or toughen protection. If we like certain aspects, we should keep them; if we don’t like certain aspects, we should amend them. Either way, it is important to understand the system in which we live.

In addition, the blog post also may have misunderstood the database’s starting point. Specifically, the post asks why the database “allot[s] ranolazine less than four months of ‘earliest’ protection time” and suggests that such a short period of protection “seems suspect.” The answer is simple. The Evergreen Drug Patent Database begins in 2005. Thus, drugs whose original patents were around a long time have little protection left when the database begins. (The blog post itself notes this history of the drug.)

Finally, the blog post questions the database’s treatment of different strengths of the drug, questioning the fact that when patents and exclusivities apply to multiple strengths of a drug, they are counted once for each instance. We chose this approach because the law prevents automatic substitution at the pharmacy counter among different strengths. In fact, shifting the market to a new strength can create a powerful method of product-hopping by blocking generic substitution. Try asking your pharmacist the cost to fill your prescription with two 25 mg tablets rather than one 50 mg tablet. The cost variations can be odd and economically irrational. In short, creating multiple strengths of a drug can provide a form of protection in and of itself. Our goal is to report as many of these aspects as possible.

In the same vein, if the brand company has shifted the market to a different strength or formulation of the original drug, delisting the original drug can be used as an evergreening technique. It can prevent generic hopefuls from obtaining samples of a brand drug, when having samples is essential for FDA approval. It also can lead health plans to reimburse the generic at the disfavored rate of brand drugs, because the generic is now the only drug on the market at that precise dosage and formulation. One could argue that a delisting request should be characterized as something other than a protection; the argument would not be unreasonable. Nevertheless, the database chronicles the Orange Book history of each drug, based on all changes recorded. We consider any delisting information to be part of a complete picture of that history.

In closing, we note that it is highly unusual for legal academics to publicly release their data, let alone at this level of excruciating detail. We do so in the spirit of academic exchange and full disclosure, and we hope that those who write for this blog, as well as those who read it, will be motivated to follow suit.

Response to Professor Feldman’s “Reply to Blog Post on UC Hastings’ Evergreen Drug Patent Search Database”

C-IP2 appreciates Professor Feldman taking time to respond to our March 4, 2021, blogpost describing some of the problems we have identified with the UC Hastings’ Evergreen Drug Patent Search Database. We have posted her response in full, in the spirit of academic inquiry and collegiality that C-IP2 strives to foster. At the same time, we want to emphasize that we do not believe that her response in fact undercuts the observations in our original post. While we agree with Professor Feldman that legal academics should release for public scrutiny the data upon which they have based their conclusions—particularly when those conclusions are intended to have some bearing on important public policy considerations—we stand by our original statement “that—because of limitations in the methodology used and given the inadequate transparency with respect to the underlying data—policymakers and others who consult the Database [could] be misled by the statistics.”

C-IP2 disagrees with Professor Feldman’s suggestion that our post “misunderstands” Hasting’s database and its starting point. The post’s description of the database as a resource that UC Hastings had created “to address the perceived problem of ‘evergreening’” reflects UC Hasting’s own description of the database. See, for example, statements on the database’s “About” page.[1] Indeed, the database is explicitly referred to on that page as “Evergreen Drug Patent Search.” One might easily be confused into thinking that the database provides information reflecting the actual period of exclusivity experienced by FDA-approved drugs, which it clearly does not.

With all due respect, Professor Feldman seems to misunderstand some aspects of the original post. For example, at one point she states that the reason the database “allot[s] ranolazine less than four months of ‘earliest’ protection time” is because the database “begins in 2005.” But the starting point of the database is irrelevant. The database reports the drug’s “Approval Date” as January 27, 2006, and the “Earliest Prot[ection] Date” as May 18, 2006, which is a little less than four months. The database goes on to report that May 27, 2019, is the drug’s “Latest Prot[ection] Date,” leading the database to conclude that the drug had received 156 “Months Add[itional] Prot[ection] Time.” C-IP2 continues to find “suspect” the database’s implied assertion that a drug that has been on the market less than four months is already benefitting from “additional protection time,” particularly when the context of the database might lead one to believe that “additional protection time” equates with “evergreening.”

 

[1] https://sites.uchastings.edu/evergreensearch/about/#.YS_g6o5KhM1

Categories
Healthcare International Law

A View from Both Sides: COVID-19, the TRIPS Waiver, IP Rights, and How to Increase the Supply of Vaccines

scientist looking through a microscopeIssue

The United States and other wealthy nations have access to plenty of COVID-19 vaccine doses and thus are beginning to get the pandemic under control, while less affluent countries do not have access to adequate doses and are still struggling with rising cases. In October 2020, India and South Africa proposed addressing this problem by waiving certain portions of the TRIPS Agreement, the most comprehensive agreement on intellectual property (IP) aspects of international trade among the WTO’s 164 member states. The waiver cites “an urgent call for global solidarity, and the unhindered global sharing of technology and know-how in order that rapid responses for the handling of COVID-19 can be put in place on a real time basis.” While this proposal broadly applies to any COVID-19-related technology, much of the conversation is currently focused on vaccines.

The proposal would temporarily suspend patent rights covering COVID-19 vaccines and possibly also be used to compel the transfer of trade secret “know-how” and “show-how.” Proponents say this would allow any manufacturer to begin production—boosting vaccine supply while slashing prices—to end the surge of cases in less developed nations. Critics argue that the reality is more complicated: the waiver will be ineffective, even harmful, and it would have a devastating impact on our readiness for future health crises.

In Support of the Waiver

For supporters of the waiver, the answer is clear: cases are rising in many nations because they still don’t have the vaccines they need. It’s only reasonable to make exceptions to our ordinary system of business incentives during times of global crisis.

The Biden Administration

That is essentially what U.S. Trade Representative Katherine Tai stated when the Biden Administration announced its support for the waiver: “This is a global health crisis, and the extraordinary circumstances of the COVID-19 pandemic call for extraordinary measures. The Administration believes strongly in intellectual property protections, but in service of ending this pandemic, supports the waiver of those protections for COVID-19 vaccines.”

It affects all of us

WHO Director-General Dr. Tedros Adhanom Ghebreyesus says that the “me-first approach” among powerful nations “is self-defeating and will lead to a protracted recovery with trade and travel continuing to suffer.” Under this rationale, even purely self-interested parties should support the waiver, if only because modern commerce is so globally connected.

Dropping IP barriers will facilitate greater collaboration

Many say the threat of IP litigation prevents the kind of collaboration needed to quickly ramp up production and development, and that a waiver can remove that threat. The president of Médecins Sans Frontières, Dr. Christos Christou, says that “[t]he waiver proposal offers all governments opportunities to take action for better collaboration in development, production and supply of COVID medical tools without being restricted by private industry’s interests and actions, and crucially would give governments all available tools to ensure global access.”

Patents were not meant to impede emergency action

A recent editorial in the journal Nature argues that patents are designed to protect ordinary commercial interests, not to hinder global cooperation against a common threat: “A pandemic is not a competition between companies, but a race between humanity and a virus. Instead of competing, countries and companies need to do all they can to cooperate to bring the pandemic to an end.”

It solves an immediate need without setting a troubling precedent

While opponents of the waiver argue that it will weaken future drug patent protection, Imron Aly and Ahmed M.T. Riaz of Schiff Hardin LLP call those concerns “unfounded” in their post at IPWatchdog. Not only is the current proposal limited specifically to COVID-19, but it was also not created carelessly. Instead, it “has taken substantial international efforts and official international law amendments.” Aly and Riaz say this exceptional action is appropriate if it can succeed where our IP system has yet to do so: “The TRIPS waiver simply allows countries the option to suspend patent enforcement to encourage COVID-19 vaccine production, which makes sense for those countries where current investment has not resulted in vaccine access.”

Even if the waiver doesn’t work, it might work

University of Houston Law Center Professor Sapna Kumar acknowledges a number of functional issues with the waiver approach but notes that it may still have a positive effect on the pandemic: “Overall, the greatest benefit of the Biden Administration’s support for the waiver is that it signals a departure from the prior approach of punishing countries facing health crises and that it might spur pharmaceutical companies to voluntarily increase out-licensing and donations of vaccines.” Her prediction was borne out by a recent pledge to donate 2.3 billion doses by Pfizer/BioNTech, Johnson & Johnson, and Moderna.

Opposed to the Waiver

Opponents of the waiver argue that it will not be effective because it fails to address the real problems. Further, it could actually be detrimental to quality control and supply chains in the present crisis, while quite possibly affecting how pharmaceutical companies choose to allocate investment dollars in the future.

It’s a long process that requires much more than a temporary waiver of licenses

Vaccines are not like other drugs. Writing for Foreign Affairs, Peter J. Hotez, Maria Elena Bottazzi, and Prashant Yadav say that we can’t compare the current situation to similar actions on HIV treatments, and that most nations are not prepared to make use of the patented technology: “Producing vaccines—particularly those as technologically complex as the messenger RNA (mRNA) inoculations against COVID-19—requires not only patents but an entire infrastructure that cannot be transferred overnight.” The authors state that “[t]he effective transfer of such complex technology requires a receiving ecosystem that can take years, sometimes decades, to build.”

We need another way

Professor Yogesh Pai of the National Law University Delhi says that simply waiving trade secret protection won’t automatically disclose everything a manufacturer needs to know. Accessing “hard tacit knowledge of manufacturing/quality control measures for production and clinical data required for regulatory clearances” could require forced technology transfer (FTT) by national governments. He recalls how detrimental such efforts were to India’s economy when it tried FTT with Coca-Cola in the 1970s, prompting the company to leave the country altogether.

Prof. Pai instead recommends efforts to encourage voluntary cooperation: “Where blunt legal instruments don’t work, using track-1 and track-2 diplomacy to place moral coercion on western governments to nudge firms to actively engage in technology licensing may still work wonders.”

“China First” policy?

Sixteen U.S. senators issued a sharply worded letter to the executive branch, questioning the true motives of “China and other countries which regularly steal American intellectual property—like India and South Africa,” and expressing shock that an American president would go along with it: “These nations are falsely claiming that granting such a waiver would speed the development of new vaccine capacity. Nothing could be further from the truth.” Instead, the senators are suggesting that the waiver is being used as a means to unfairly to acquire trade secrets that took massive resources and time to develop.

Reuters reports that “some U.S. officials fear the move would allow China to leapfrog years of research and erode the U.S. advantage in biopharmaceuticals” and quotes a senior U.S. official as saying that the country “‘would want to examine the effect of a waiver on China and Russia before it went into effect to ensure that it’s fit for purpose.’”

IP is not the Issue

A waiver on patent rights, even with the corresponding trade secrets, can only give permission to manufacture. But Eva Bishwal of Fidus Law Chambers writes that the real problems in India “are state inaction, dearth of raw materials and low production capacity.”

According to Patrick Kilbride of the U.S. Chamber of Commerce’s Global Innovation Policy Center, and as cited in Pharmaceutical Technology, “[p]roposals to waive intellectual property rights are misguided and a distraction from the real work of reinforcing supply chains and assisting countries to procure, distribute and administer vaccines to billions of the world’s citizens.”

Low-quality vaccines could do more harm than good

Former USPTO Director Andrei Iancu voiced concern recently at a World IP Day event, asking, “if we waive IP rights, and exclude the original manufacturers, how are we going to control the quality of the vaccines that go into people’s arms? How are we going to control for the fake vaccines? Just last week we saw fake Pfizer vaccines.” And as Philip Thompson points out for IPWatchdog, when investigators are forced to “determine if adverse events or sub-par effectiveness originate from ‘real’ vaccines or fake doses, we should expect global production starts and stops to become much more frequent.”

It will discourage investment in the most critical areas

Pharmaceutical developers invest unfathomable amounts of money into bringing drugs to market. The path to success is long, expensive, and highly uncertain. But what is certain is that successful drugs can yield a profit that covers the loss from failures. Now critics are deeply worried that this waiver will skew future cost-benefit analyses against important classes of medicine. All other things being equal, a developer has a better chance at a positive return by investing in drugs that pose no risk of seizure during a global emergency. As Amanda Glassman of the Center for Global Development writes, the waiver sends the wrong message to innovators and investors: “don’t bother attacking the most important global problems; instead, throw your investment dollars at the next treatment for erectile disfunction, which will surely earn you a steady return with far less agita.” The scramble amongst pharmaceutical giants to develop a vaccine was an all-out race, with good reason, and that’s exactly how it should be. If those companies believe that forfeiture is waiting at the finish line next time around, we might see fewer contestants.

Even “no-profit” vaccine makers appear to oppose the waiver

Pfizer CEO Albert Bourla laid out everything the company has done to combat the vaccine in an equitable manner and argued that “waiver of IP rights could only derail this progress.” And while Pfizer and Moderna are selling their vaccines at a profit, Johnson & Johnson and AstraZeneca have pledged not to do so during the pandemic.

However, it appears that even those companies oppose the waiver. As reported in The Wall Street Journal, the trade group PhRMA, which represents Johnson & Johnson and AstraZeneca among many others, is “lobbying members of Congress to oppose the Biden administration’s support for the waiver.” Johnson & Johnson’s Chief IP counsel Robert DeBerardine says that patent rights are responsible for the breakneck pace of development and that the drug’s makers are the best-equipped people to continue the fight: “What we’re able to do, because we have control of the IP, is to pick the best companies to help us supply the world. If you were to give everything to everybody, you may see a flood of vaccines, but you would have no idea if they’re safe and effective.”

Conclusion

While we share the concerns of other organizations that effective, affordable, and accessible vaccines be made available to all persons regardless of location or wealth, we do not believe that upending longstanding U.S. patent policy for a solution that will do little if anything to increase the vaccine supply is advisable. Strong IP rights remain the best way to incentivize innovation and ultimately increase the supply of life-saving medicines. The Biden administration’s unprecedented support of the proposed WTO IP waiver, while well intended, is likely to create long-term harm and unlikely to have much of an impact on global vaccine supplies. Ultimately, encouraging companies to license IP and engage in voluntary knowledge transfer, along with the sharing of excess doses that are being produced, are methods far more likely to alleviate the vaccine supply issues than waiving IP rights and would be a better path forward out of the current crisis.

Categories
Patents Pharma

UC Hastings’ Evergreen Drug Patent Search Database: A Look Behind the Statistics Reveals Problems with this Approach to Identifying and Quantifying So-Called “Evergreening”

Professor Robin Feldman’s reply to this post, and our response, can be read read here.

pharmaceuticalsThe Center for Innovation, housed at the University of California Hastings College of the Law, has created an Evergreen Drug Patent Search Database (the “Evergreening Database,” or “Database”).[1] The Database was created to address the perceived problem of “evergreening,” which the Database defines as “pharmaceutical company actions that artificially extend the protection horizon, or cliff, of their patents.”[2] Its data include patent and non-patent exclusivity information from out-of-date versions of the FDA’s Orange Book.[3] The implication seems to be that these statistics, which include things like the number of “protections” and “extensions” associated with a drug, and the amount of “additional protection time” resulting from these protections and extensions, serve as indicia of evergreening, which the Center for Innovation characterizes as a “problem [that] is growing across time.” The Database’s homepage explains that “[t]he Center for Innovation hopes that policymakers and other stakeholders use this information to identify potential problems with evergreening and develop new solutions so that anyone and everyone can access the life-saving medication that they need.”

Based on our preliminary exploration of the Evergreening Database, we are concerned that—because of limitations in the methodology used and given the inadequate transparency with respect to the underlying data—policymakers and others who consult the Database will be misled by the statistics. While the Database allows the public to access the underlying data, the format in which the data are provided makes the process of accessing and understanding them relatively burdensome.

The problems we have identified with the statistics provided by the Evergreening Database are numerous and multifaceted, and it would be beyond the scope of a single blog post to try to address them all. Instead, we have decided to focus on a single drug, ranolazine, which is used to treat angina and marketed by Gilead under the tradename Ranexa. There is nothing particularly unique about ranolazine—the problems with its statistics are representative of what we have generally observed to be pervasive throughout the Database. The ranolazine entry caught our attention because it purports to show that the drug was a subject of a relatively large number of “protections” (24 of them) and 13 years of “additional protection time,” even though the total time between the approval of the drug and expiration of all associated patents and exclusivities was only a little more than 13 years—about five years less than the average term of a U.S. patent.

We will start with an initial explanation of the methodology underlying the Evergreening Database. As mentioned above, the statistics are derived from out-of-date versions of the FDA’s Orange Book, which is published on the FDA’s website and provides information on patents and “exclusivities” associated with FDA-approved drugs. The exclusivities can be any of a variety of non-patent regulatory exclusivities that Congress created to reward innovators that have achieved certain outcomes that Congress sought to incentivize. Examples include the “NCE exclusivity”—five years of data exclusivity awarded for the initial approval of a new active ingredient, i.e., a “new chemical entity”—and the seven years of orphan drug exclusivity awarded to an innovator that develops a drug for a rare disease or condition. The Orange Book provides a listing of these exclusivities, as well as a list of patents relating to the approved drug (i.e., patents claiming the drug’s active ingredient, formulations of the drug, and methods of using the drug). It also provides expiration dates for the patent and exclusivities. The FDA periodically revises the Orange Book, and when it does, it removes from the lists any patents and exclusivities that have expired.

The creators of the Evergreening Database compiled this historical data in a Comma Separated Values file (“the CSV file”). The Database uses the patents and exclusivities derived from the CSV file to generate various statistics for each drug, including a total number of “protections” and “extensions,” as well as the “earliest protection date,” “latest protection date,” and the number of “months of additional protection” (which is the time between the earliest protection date and the latest protection date). Presumably, these statistics are intended to shed some light on the purported evergreening practices of pharmaceutical companies.

Now let us turn to ranolazine. The Evergreening Database entry for ranolazine provides the New Drug Application (“NDA”) number for the drug (21526), the branded product name (Ranexa), the name of the innovator company associated with the branded drug (Gilead), and the date of FDA approval (January 27, 2006). The ranolazine entry also provides various statistics derived from the raw data, including the number of “protections” (26) and the amount of “additional protection time” (156 months, i.e., 13 years). This seems to provide an example of evergreening. The statistics appear to show that Gilead gamed the system to “artificially extend the protection horizon of its patents” by 13 years. However, a closer examination of the raw data tells a quite different story.

First, what are the 26 purported “protections” that Gilead has apparently secured with respect to Ranexa? Eleven of them are patents that were once listed in the Orange Book for the drug. All the listed patents have expired, so none appear in the current Orange Book. While the Database lists the patents, it does not include expiration dates, which are necessary to understand the “protection time” statistics. Worse, the Database provides no information with respect to the other 15 “protections,” i.e., non-patent exclusivities.

With some effort, the missing information can be found in the CSV file. The following step-by-step instructions will hopefully make it easier for others interested in following this path.

Beginning on the homepage for the Evergreening Database, click on the “About the Data” hyperlink, which will take you to another page which states:

To download the original dataset, that was used to develop the results for the article May Your Drug Price Be Evergreen, along with information about researching the FDA’s Orange Book, please see:

Robin Feldman, Identifying Extensions of Protection in Prescription Drugs: Navigating the Data Landscape for Large-Scale Analysis, ANN ARBOR, MI: INTER-UNIVERSITY CONSORTIUM FOR POLITICAL AND SOCIAL RESEARCH (2018), https://doi.org/10.3886/E104781V2.

Clicking on the “doi.org” link leads to a webpage of “openICPSR,” which describes itself as “a self-publishing repository for social, behavioral, and health sciences research data” and a “service of the Inter-university Consortium for Political and Social Research (ICPSR).”

There are several files posted on this webpage, including one entitled Orange_Book.csv. Users can download this file after registering with openICPSR.

The CSV file includes 26 entries for ranolazine that presumably correspond to the 26 “protections” reported in the Database. All 26 protections were based either on the eleven patents or on the NCE exclusivity granted by FDA for the first approval of a new active ingredient. How does that add to 26 protections? Each of the 11 patents was counted twice, once for each approved strength of the drug (which comes in dosages of 500 mg and 1 g). However, marketing approval for two strengths of a drug does not extend the duration of the patents, and it is problematic that the methodology underlying the database results in a doubling of the number of “protections,” with the implication that this constitutes evidence of possible evergreening.

One of the patents (U.S. patent number 4,567,264) was counted as three protections, because the duration of that patent was extended by patent term extension (PTE) pursuant to Section 156 of the Patent Act. Congress enacted Section 156 in 1984 as part of the Hatch-Waxman Act for the express purpose of addressing the “distortion” of the patent term experienced by pharmaceutical innovators owing to the lengthy process of achieving FDA marketing approval. Often, by the time a drug has been approved, much (if not all) of the patent term will have elapsed. To compensate for this distortion, Section 156 allows pharmaceutical innovators to extend the duration of one patent covering the drug by a length of time equal to one half of the time between the filing of the Investigational New Drug (IND) application and the submission of an NDA, plus all the time between the submission of the New Drug Application (NDA) and approval of the drug. Pursuant to statute, the maximum amount of PTE that can be awarded under Section 156 is five years, and the amount of PTE awarded can extend the duration of the patent for no longer than 14 years after the drug’s approval date.

Five years of PTE was added to U.S. patent number 4,567,264, which claims ranolazine as a composition of matter. Notably, the original expiration date of this patent was in 2003, three years prior to the drug’s initial approval. With the addition of five years of PTE, the patent term was extended to 2008, a little more than two years after the drug was approved for marketing. But since the patent term (including PTE) runs concurrently with the five-year NCE data exclusivity (discussed below), the patent provided no additional exclusivity beyond that already provided by NCE exclusivity. The Database is misleading to the extent that it implies that the award of PTE constitutes an “artificial” extension exclusivity for ranolazine—PTE was created by Congress for this express purpose, and it is available to all innovators who make a new drug available to patients.

One of the 26 “protections” was simply a request to delist a patent from the Orange Book. It makes no sense to consider a request to delist a patent as an additional “protection” for the drug, but for some reason that is how it is tallied in the CSV file and Database.

To summarize, 24 of the 26 “protections” are accounted for by the 11 patents, including the award of PTE and the request to delist a patent. The remaining two “protections” result from the fact that Gilead received five years of NCE data exclusivity. Like the patents, the NCE exclusivity period was counted twice, once for each approved strength of the drug. Congress created NCE exclusivity as an incentive for pharmaceutical companies to engage in the costly and beneficial activity of securing FDA approval for new pharmaceutical active ingredients, thereby ensuring that innovators receive a minimum of at least five years of exclusivity before any generic company can file an abbreviated NDA (ANDA) seeking approval to market a generic version of the drug. All innovators who succeed in providing a new active ingredient to patients are awarded five years of NCE exclusivity, which runs concurrently with patents. Again, it is misleading for the Database to tally the NCE exclusivity as two additional “protections” for the drug. NCE exclusivity provides a minimum floor of protection for innovators.

Now, what about the 11 patents? Are they evidence of evergreening, i.e., artificial extensions of patent protection? In assessing these patents, it is useful to consider the context from which they arose. Ranolazine was initially identified as a drug target by Syntex in the 1980s, and throughout much of the 1980s and 1990s that company conducted extensive studies of the compound for a variety of indications, including Phase II clinical trials testing its safety and efficacy in humans. Unfortunately, these studies failed to result in an approved drug, due at least in part to the fact that ranolazine is rapidly metabolized once ingested, which resulted in inadequate plasma concentrations of the drug in human subjects. Syntex filed a patent application disclosing ranolazine in 1983 that resulted in the issuance of a patent in 1986 claiming the molecule. This is the composition of matter patent mentioned above, the original term of which expired in 2003 but was extended by PTE to 2008.

In 1996, Syntex (then a subsidiary of Roche) licensed its rights in ranolazine to another drug company, CV Therapeutics. Researchers at CV Therapeutics succeeded in overcoming the problem of rapid metabolism by developing a sustained-released version of the drug. In 1999, the company filed a patent application disclosing sustained-release ranolazine formulations and methods of using them to treat patients. This application resulted in the issuance of a patent in 2001 claiming methods of using the sustained-release formulation of ranolazine to treat patients suffering from angina (U.S. patent number 6,306,607, the “method of treatment patent.”, which expired in 2019). Note that the method of treatment patent was issued years before the initial FDA approval of ranolazine in 2006, and the initial approval was for the sustained-release ranolazine. Generic versions of ranolazine began entering the market in 2019, shortly before the expiration of the method of treatment patent.

What about the other nine? All nine of these patents arose out of continuation applications claiming priority to the original 1999 application and therefore expired on the same day as the method of treatment patent, i.e., 20 years after the filing date of the original parent application. The nine additional patents reflect the fact that the 1999 patent application filed by CV Therapeutics disclosed multiple inventions, addressing different aspects of the company’s discovery of sustained-release ranolazine formulations and their use as therapeutic agents. Patent law’s prohibition against “double patenting” required CV Therapeutics to divide the inventions up into multiple patents, and the PTO examined the various inventions and determined that each merited its own patent. Significantly, because the patents all ran concurrently, and all expired on the same day, they did not extend the period of exclusivity beyond that provided by the initial method of treatment patent.

Finally, what of the Database’s assertion that Gilead benefited from 13 years of “additional” protection time for Ranexa? Presumably, this is time gained from “evergreening”; however, the statistics provided by the Database seem suspect, because they report that Ranexa was approved on January 27, 2006 (which is correct), that its “earliest protection date” was May 18, 2006 (less than four months later), and that its “latest protection date” was May 27, 2019 (which is the expiration date for the method of treatment patent). In other words, the total period of exclusivity reported by the Database was a little less than 13 years and four months, almost all of which the Database characterized as “additional protection time.”

Why did the Evergreening Database allot ranolazine less than four months of “earliest” protection time? There is no explanation in the Database itself, but the CSV file provides the answer. As mentioned earlier, the CSV file includes three entries for the composition of matter patent, accounting for three of the 26 “protections.” One of those entries lists the “expiration date” for the patent as May 18, 2006. It is this entry in the CSV file that resulted in the Database reporting an “earliest protection date” of May 18, 2006, less than four months after the drug was approved. The latest protection date of May 27, 2019 is the expiration date for the method of treatment patent. The 13 years of “additional protection time” is simply the amount of time between these two dates.

There are numerous problems with the methodology used to calculate “additional protection time.” For one thing, the May 18, 2006, expiration date for the composition of matter patent reported in the CSV file is incorrect. The expiration date for the patent was May 18, 2003, and the term was extended by five years of PTE to May 18, 2008 (see the PTO’s Patent Terms Extended Under 35 USC §156, available at https://www.uspto.gov/patent/laws-and-regulations/patent-term-extension/patent-terms-extended-under-35-usc-156, last visited Nov. 29, 2020). The two other entries in the CSV file for the composition of matter patent provide expiration dates of May 18, 2007. We assume that the creators of the Database intended to populate the CSV file with the original expiration date of the patent and the PTE-extended expiration date, but for some reason they got the years wrong—i.e., the actual years were 2003 and 2008, and the creators of the Database erroneously reported them as 2006 and 2007.

However, because they used the erroneous May 18, 2006 expiration date as the “earliest protection date” for ranolazine, the Database allows for less than four months of “earliest” protection time and counted the remaining 13 years of protection provided by the method of treatment patent as “additional.” In fact, if they had used the correct original expiration date for the composition of matter patent, the result would have been an “earliest protection date” that preceded the approval date of the drug, resulting in zero days of initial protection. This illustrates how misleading it would be to assume there is any connection between the “additional protection time” reported in the Database and evergreening activity.

In short, when we look at the raw data underlying the misleading statistics presented by the Database, we see that the innovator enjoyed a little over 13 years of patent protection, based on patents that arose out of the critical inventive activity that enabled CV Therapeutics to transform a failed drug candidate into a successful human therapeutic. Is 13 years of patent protection excessive for ranolazine? We would argue that it is not, particularly when one considers the huge investment and risk that was involved in bringing the drug to market. And Congress did not think so when it enacted Section 156, explicitly allowing pharmaceutical companies to extend the expiration date of their patents up to a maximum of 14 years after initial approval of the drug. The patent system appears to have worked exactly as Congress intended, with all patents and exclusivities expiring and generic versions of the drug entering the market approximately 13 years after the initial approval of Ranexa.

There may be real value in the underlying data that were used to generate the database; however, as it stands, the underlying data are both difficult to access and incomplete. As Ranolazine shows, there are serious flaws in the database and its interpretation of the underlying data that create unwarranted implications of improper evergreening activity.

[1] https://sites.uchastings.edu/evergreensearch/#.X6qg-mhKhM0

[2] https://sites.uchastings.edu/evergreensearch/about/#.X8UdwmhKhM0

[3] In proper context, use of these data from old Orange Book editions is of course fine. But care must be taken to not create misleading implications.