Fellow Jake Sherkow on the Indian Supreme Court Gleevec decision;
Fellow Matt Lamkin on disability law and social realities;
and himself on the ethical issues surrounding the sequencing of the HeLa genome.

You can hear the podcast, here:

Podcast No. 8

The format is simple–each has ~500 words of opening statement followed by ~250 words of rebuttal. You decide which Jacob is right. (Or if both are. Or, if neither.) As Jacob Rooksby is the away team, he gets to bat first, while Jake Sherkow gets “last licks.”

Rooksby’s Opening Statement

The FDA’s determination is sensible.  It recognizes the original OxyContin®’s abuse limitations and the attendant public safety risks of allowing generic versions of the original drug to enter the market.

OxyContin® (oxycodone hydrochloride) quickly became the market leader in the burgeoning field of chronic pain management when the FDA approved it for sale in late 1995.  Touted for its patented sustained-release properties, OxyContin® allowed patients to obtain 12-hour pain relief, compared with 4 to 6 hours from one tablet of immediate-release oxycodone.

While the drug’s advantages were many, it also had drawbacks.  Users or third parties could easily abuse the drug by breaking, chewing, crushing, injecting, or burning it, thereby defeating its sustained release properties and achieving a heroin-like high.  By the late 1990s, stories of pharmacies being robbed for the product, and teenagers becoming addicted to it, were rampant.  Rural areas in particular saw unusually high rates of prescriptions being written for the drug, and correspondingly high rates of abuse.

Many blamed Purdue for this epidemic and the deaths that resulted.  Purdue had aggressively marketed the blockbuster drug, which earned the company over $1 billion in revenue a year by the early 2000s.  In a federal criminal case, Purdue officials ultimately pleaded guilty in 2007 – individually and on behalf of the company – to charges that they misled the public about the drug’s risk of addiction and its abuse potential.  Other legal battles included hundreds of products liability actions and a robust challenge to Purdue’s patents on OxyContin® brought by a generic manufacturer.  While Purdue initially lost at the trial and appellate levels, the Federal Circuit ultimately vacated a finding unfavorable to Purdue, and the company soon settled on terms that protected its monopoly.  Meanwhile, Purdue invested millions in creating an abuse-deterrent OxyContin® that is bioequivalent to the original formulation, a feat it achieved in 2010 when the FDA allowed Purdue to replace original OxyContin® with the new formulation, which turns gummy if tampered with.  [Full disclosure: I defended Purdue in a patent dispute brought by King Pharmaceuticals in 2008].

The FDA’s labeling decision recognizes this history.  From a practical standpoint, the FDA must incent companies like Purdue to invest in safer products, and its decision to prevent generic entry can be viewed as furthering this objective.  From a normative perspective, if a new formulation renders a drug substantially safer than a previous version, the public should not have access to the original, much like one cannot buy new cars without seatbelts.  While many individual consumers who used original OxyContin® as intended no doubt would prefer access to it at generic pricing, these desires must be counterbalanced by the real harm that comes to abusers simply from being able to obtain the drug somewhere.  Some risks are too great to allow the public to assume them on their own, in the interest of low prices.  The FDA’s job is to weigh individual consumer interests in competition against safety considerations that further the public good.  In not permitting an open market for an abuse-prone formulation, the FDA made the right decision here.

Sherkow’s Opening Statement

Purdue Pharma currently sells OxyContin, its patented formulation of the popular pain killer, oxycodone. So popular, in fact, that OxyContin has become one of the most widely abused prescription drugs in history. Entire states, such as Ohio and Kentucky, saw spikes in overall crime rates attributable specifically to OxyContin abuse. Fueling much of the abuse was the ability to crush and snort high-dosage formulations of OxyContin, bypassing the formulation’s time-release effect, and delivering a powerful high. Many abusers described snorting “Oxy” as “better than heroin.” At the same time, for patients with particularly acute pain, physicians have called the medication a “miracle drug,” enabling many sufferers to return to normal, pain-free lives. In total, OxyContin netted Purdue $3 billion a year until 2009.

To Purdue’s credit, beginning in the mid-2000s, it began research into formulations that would prevent OxyContin abuse by making its pills impossible to crush. That formulation was eventually patented and went on the market in 2010. Some evidence has shown that drug-users have found their kicks elsewhere.

But Purdue’s main OxyContin patent, U.S. Patent No. 5,508,042, was set to expire on April 16th of this year, and as such, it faced stiff competition from generics who wished to sell the older, potentially abusable formulation. So, rather than risk any portion of its $2.5 billion market share, Purdue switched the formulation of the “reference listed drug” to the new formulation, and then petitioned the FDA to—get this—declare its previous formulation “unsafe,” even though Purdue had been selling it, hand over fist, since 1995.

Somewhat surprisingly, it worked. On April 16, 2013—the day Purdue’s ’042 patent was set to expire—the FDA announced that “the benefits of original OxyContin no longer outweigh its risks and that original OxyContin was withdrawn from sale for reasons of safety or effectiveness. Accordingly, the agency will not accept or approve any abbreviated new drug applications (generics) that rely upon the approval of original OxyContin.” The end result, of course, is Purdue gets to continue its monopoly of OxyContin under the guise of “patient safety,” while true pain suffers who have never abused this “miracle drug” must continue to pay Purdue’s rents for at least another five years.

Aside from the fact that Purdue seems to have known about and hid information about OxyContin’s potential for abuse from the FDA, there is the issue of what scholars call, “regulatory gamesmanship.” Simply put, using the FDA’s own regulations to peddle a patented and profitable formulation of a drug for years, and then using those same rules to prevent competition by declaring the old formulation “unsafe” has little to do with any real concerns about patient safety and everything to do with profit. For if it did, Purdue would have neither waited until the 11th hour of its patent exclusivity to conduct such research, nor swapped its OxyContin’s reference listing to prevent generic entry.

The public deserves better. OxyContin abuse may have been rampant, but hundreds of thousands Americans—responsible Americans—took the drug to get back to their lives rather than getting high. And of these, most, if not all, were in pain severe enough to take the drug in the first instance. Now that Purdue’s primary patent has expired, they should not be prevented from or pay monopolistic rents to take the exact same drug they’ve been taking all this time. Nor, for that matter, should Medicare and Medicaid foot a continually expensive bill. Drug abusers shouldn’t control the market for generic medications. And nor, for that matter, should regulatory gamesmanship.

Rookby’s Rebuttal

Regulatory work is an imprecise exercise in cost-benefit analysis.  No drug would be approved if perfection were the standard.  Therefore, the FDA acts appropriately when it acts reasonably, in light of available information.  With respect to OxyContin®, unquestionably the FDA’s recent decision meets this standard.  When OxyContin® was first approved, the patented extended-release formula offered many benefits to patients suffering from chronic pain.  These benefits continued to outweigh the drug’s limitations until a tamper-resistant formulation – with the same positive attributes as the original – was developed.

Creating one was no easy feat, and publicly-available evidence indicates that Purdue did not embark on such research at the “11th hour” in an attempt at “regulatory gamesmanship.”  Patents such as Nos. 6,696,088 (filed in 2001) and 7,658,939 (filed in 2003) represent early, good faith efforts by Purdue to address the original OxyContin®’s safety limitations.  That these efforts did not immediately bear fruit for Purdue in the form of a commercially viable product says more about the constraints of dosage form design for opioids than it does about Purdue’s intentions.  To make a tamper-resistant oxycodone formulation is not difficult.  But to make a tamper-resistant oxycodone formulation bioequivalent to the original OxyContin® – so that responsible users in need are not deprived of the extended pain relief of the original formulation – is what took Purdue years of effort and $100 million in research investment to achieve.  The FDA’s public safety concerns flow to users and abusers alike.

Finally, it bears noting that consumers who want access to the reformulated OxyContin® at generic prices will not have “to pay Purdue’s rents for at least another five years.”  As part of a settlement of a patent dispute between Purdue and Actavis, Actavis will be permitted to offer a generic version of the reformulated drug in 2014.

Sherkow’s Rebuttal

Ultimately, I think Jacob and I agree on many things. (I’ll let you mull that sentence over for a moment.) We agree the old formulation is prone to abuse. We agree that the new formulation seems to be genuinely focused on curbing that abuse. And we agree that it’s important to encourage companies to develop safer formulations of drugs. Where we part ways, it seems, is on whether Purdue’s actions in developing, patenting, and marketing OxyContin—and de-developing, re-patenting, and re-marketing the new formulation—are worthy of full-scale, market exclusivity. And the answer, I think here, is a clear, No.

First, it’s critically important to distinguish between the two types of “public safety” at issue here. Neither the drug nor the old formulation is, itself, “unsafe.” The older formulation was only unsafe for recreational purposes. And that is traditionally not the sort of “safety” the FDA is concerned with. Countless prescription drugs are used recreationally, and some, with side effects not present in their “as directed” use. But the FDA does little, if anything, to prevent generic competition of those drugs. Nor should they. We would be appalled if, every time a drug company came up with an abuse-resistant formulation, generics would be precluded from selling their wares.

Second, there were numerous ways to encourage drug companies to develop abuse-resistant formulations of OxyContin, and Purdue clearly took advantage of one of those ways: patents. Purdue’s patents on its new formulations do not appear to expire until 2025—twelve years from now—at the earliest. But patenting a “safer” formulation of drug should only prevent sales of the “safer” formulation, not generics of the older formulation—even if it is abused by some. Physicians concerned about patients who may abuse the drug then have an easy choice—to prescribe, “DAW,” the new formulation. Patients who don’t present such concerns should not be limited in their choice of medication.

Simply put, this just isn’t like cars and seatbelts because it’s not about “public safety”–it’s about regulatory gamesmanship, plain and simple. And Purdue’s actions should be treated like the car wreck they truly are.

- SLS 1L, Amanda Rubin, on the annoucement of President Obama’s Brain Map Initiative;
- SLS 1L, Roland Nadler, on the electrifying work of transcranial direct current stimulation;
- Fellow Jake Sherkow on the less electrifying, but still very important, Amgen v. Connecticut Retirement Plans case decided by the Supreme Court;
- and himself on mice with human neurons.

You can hear the podcast, here:

Podcast No. 7

(And music bumper information can be found here.)

Mini-Podcast with Shubha Ghosh

To briefly recap the facts: In 1994, researchers at the University of Utah discovered that several mutations in the genes BRCA1 and 2 corresponded to a significantly elevated risk of breast and ovarian cancer. They patented various aspects this discovery, such as methods for using the sequence of these mutations to test for breast cancer, a kit to perform that test, and–now at issue before the Supreme Court–the “genes” themselves. In reality, the claims directed toward the genes were of a variety of types: the genes isolated from chromosome 17, the so called “isolated DNA” claims; the same genes as in the isolated DNA but missing their non-coding portions, or the cDNA (cloned DNA) claims; and primers, or short DNA sequences, 15 nucleotides in length, used to clone BRCA1 and 2. The researchers then exclusively licensed their patents to Myriad Genetics.

Out of concern, a consortium of BRCA researchers, labeled the Association of Molecular Pathology, in conjunction with the ACLU, filed suit against the PTO and Myriad Genetics to invalidate the patents. The district court had concluded that almost all of Myriad’s patents’ claims were invalid, but, on appeal, the Federal Circuit mostly reversed, affirming only the district court’s invalidation of one type of method claim. The parties petitioned the Supreme Court for certiorari in 2011, which, in 2012, the Supreme Court granted, vacated, and remanded in light of Mayo v. Prometheus. On remand, the Federal Circuit issued an almost identical decision, which the parties again appealed, and the Supreme Court again took up.

The lead petition presented three questions: (1) Are human genes patentable? (2) Did the court of appeals err in upholding a method claim that is irreconcilable with Mayo?; and (3) a question related to the extent of declaratory judgment jurisdiction after MedImmune. Interestingly, the Court limited its acceptance of the case to the first and, consequently, broadest question–not its typical practice.

Based on the Court’s acceptance of this loaded question–and based on Justice Breyer’s recent foray into patent law–good money going into the argument was on the Court striking down Myriad’s gene claims. Christopher A. Hansen, of the ACLU, argued in favor of AMP; the government, who requested an appearance in this case, was represented by Solicitor General Donald J. Verrilli; and Gregory A. Castanias, of Jones Day, argued for Myriad.

Mr. Hansen began, and lead his argument with the proposition that Myriad didn’t actually invent anything; it unlocked the secrets of two genes but that those were not, themselves, patentable inventions. This led to some strange confusion among the Justices about the difference between product and product-by-process patents, which in turn led Mr. Hansen to respond that if the product were identical to that found in nature, a product-by-process patent would be unobtainable as well. This then led to some brief confusion among the judges as to whether invalidated claims were divisible from the remainder of the patent. (The answer is Yes, as explicitly stated in 35 U.S.C. § 288.) Seeming to lead this conversation away from a morass of confusion, Justice Kagan then asked Mr. Hansen to respond to the incentive issue–whether anyone in Myriad’s position would have invested in such research were it not for the possibility of patent protection. Mr. Hansen attempted to suggest that scientific curiosity would normally play a role, but it appeared that the Justices rejected this position. Mr. Hansen then tried to flip the issue on its head, suggesting that DNA patents in fact hindered the commercialization of other, similar recombinant DNA, but it was unclear whether the Justices agreed with that either.

Out of this mire, Justice Sotomayor jumped in, and cut straight to the heart of the matter, asking why cDNA, as a synthetic molecule, should not be patentable. In doing so, the Justice nailed the cDNA synthesis process perfectly, even up to saying the words “introns” and “exons,” perhaps a Supreme Court first. Mr. Hansen’s response suggested that this was essentially no different from what happened in nature, because the exon removal process–also known as splicing–occurred in the cell’s transcription of DNA to mRNA. (Side point: This is technically incorrect; splicing occurs either immediately following transcription or during post-transcription processing, not during transcription itself.)  Justice Breyer then fumbled around with what seemed like a meaningless distinction between RNA’s inclusion of uracil rather than DNA’s thymine.

This all then led to the greater question of whether this case wouldn’t be more properly received under nonobviousness rather than patent eligibility. Hansen partially disagreed, saying that it was the sequence that made these genes valuable, and that that sequence was no different from that found in nature, and therefore more a matter of eligibility rather than nonobviousness. Justice Breyer again pressed a point about the chemical differences between cDNA and DNA, but Mr. Hansen reminded him that the patent defined “DNA” as including both.

General Verrilli then took the podium, and took up the cause that while isolated DNA should not be patentable, cDNA should be. Justice Sotomayor, quickly becoming an existentialist, then asked, “Are we fighting over nothing?” lamenting the lack of a significant difference between the two, at least in this case. The argument then again turned to whether obviousness was a better invalidator than eligibility. General Verrilli stated simply, that the Court’s own precedents appeared to make it so, and refused to express an opinion–exercising his amicus’s privilege–on whether the government believed the patents would nonetheless be invalid for obviousness. Justice Alito then expressed his concern that eligibility was, essentially, the broadest question, and if the Court could avoid resolving it, that would seem to be for the best.

Mr. Castanias then began his argument but was quickly cut off by Justice Sotomayor. Justice Sotomayor asked him to respond to the contention that gene sequences–the heart of Myriad’s patents–were little more than binary sequences, which the Court had long held unpatentable. Mr. Castanias disagreed, analogizing them to new chemical compounds–things–as opposed to abstract ideas. Justice Breyer then attempted to clarify whether tiny portions of isolated DNA molecules were in fact present in cells as a probabilistic matter. Mr. Castanias then tried to analogize the case to carving a baseball bat (patentable) from a tree (unpatentable), which then led to Justice Alitor’s hypothetical of whether it would matter that a piece of driftwood, sometime in geological history, happened to be exactly like a baseball bat. Mr. Castanias then tried again, comparing the gene to the extract of an exotic Amazonian plant, rather than the plant itself, which seemed to only lead to more confusion as to whether Myriad’s gene patents were more like the extract or the plant. When this all failed–through, it seems, much more the fault of the Justices than Mr. Castanias–Mr. Castanias relied on that all stalwart of prudence–reliance–claiming thirty years of it when it came to DNA patents. The Justices, still enamored with the various analogies being pasted on the walls, tried for another: isolating an organ from a human body. Was the organ patentable? Mr. Castanias answered No–because it performed the same function as the organ inside the body.

Mr. Hansen, with his reserved time, again took the podium, and Justice Sotomayor pressed him for a Yes or No answer to whether isolated DNA, as opposed to cDNA, was patentable. Mr. Hansen answered No, and his response ensued into a debate as to whether cDNA is “recombinant DNA,” a question that seemed to turn, in the Justices’ minds, as whether nature or a scientist decided the cDNA’s sequence. Mr. Hansen pressed his nature point, but–like much of the rest of the argument–it became further lost in analogies.

————————–

Reading oral argument tea leaves is always a difficult proposition. And Breyer–who many had pegged as the Court’s anti-intellectual property stalwart–seemed, only next to Justice Alito, to provide the most salient (if scientifically inept) defense of some of Myriad’s claims. Nonetheless, I count at least five votes decidedly on board to invalidate Myriad’s claims: Chief Justice Roberts, and Justices Kennedy, Ginsburg, Sotomayor, and Kagan. All bets are off when it comes to Justice Scalia and anything scientific, and Justice Thomas has, much to many’s surprise, shown to be an apt and even-handed student of the history of patent law. And lastly, Justice Alito seemed ready to defend Myriad’s claims to their logical absurdities.

So, like so many other revolutions before, the Breyer revolution in patent law may have claimed its leader.

Mini-Podcast with Andrew Torrance

On February 10, 2013, Nature Medicine published an article, which discloses that the partially disabled cowpox virus, known as JX-594, has been shown to combat cancer. Scientists have manipulated the vaccinia virus by removing the self-replicating gene and inserting another gene that helps recruit immune cells to cancerous tumors, thereby creating the engineered virus JX-594.

In a randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594, scientists were able to prolong the lives of 30 terminally-ill liver cancer patients. Each patient was given either three large doses or three small doses of JX-594 into their liver tumors over the span of a month. Approximately, sixteen patients received the large doses while 13 patients received the small doses. Researchers found that those receiving the large doses possessed an average of median survival of 14.1 months compared to the 6.7 months exhibited by patients receiving the small doses. At least four patients survivied for more than two years and those survivors included two patients whose tumors did not respond to medication.

As such, there is discussion regarding the use of JX-594 as a tool for combating chemotherapy and other drug-resistant cancerous tumors, as it works by recruiting immune cells to attack cancerous tumors. Currently, the National Institute of Health (NIH) has granted Jennerex Biotherapeutics an exclusive license for the development of oncolytic viral cancer therapies. The license grants exclusive rights to Jennerex Biotherapeutics to manufacture these viruses for the treatment of human cancers. It essentially encompasses the modified engineered viruses and the methods and techniques that allow the practical use of these viruses for cancer treatment.

As per 35 U.S.C. 209(a), a federal agency, such as the NIH, may grant an exclusive or partially exclusive license on a federally owned invention only if granting the license is a reasonable and necessary incentive to: (A) call forth the investment capital and expenditures needed to bring the invention to practical application; or (B), otherwise promote the invention’s utilization by the public.

The Association of Molecular Pathology (AMP) has in certain cases opposed such exclusive grants. In 2011, the AMP opposed the NIH’s proposal to exclusively license cancer-related proteonomics to a private entity. AMP’s rationale was that no one company should be given this amount of breadth as the license allows the private company to monopolize medical information. Granting an exclusive license means that the private company controls the costs of developing cancer-related proteonomics, while decreasing patient access to diagnostic tests and discourage innovation in this area. It would stifle medical research regarding cancer-related proteonomics.

According to the AMP newsletter, “such a license must serve the best interests of the public; must be a “reasonable and necessary” incentive for the attraction of investments required to bring the invention to practical application; and must not lessen competition.” Additionally, “practical application of the invention must be unlikely under a nonexclusive license, and the scope of exclusivity cannot be broader than is necessary to bring the invention to practical application.”

What exactly then is the public’s interest? Several licensing agreements have overcome this hurdle by agreeing to pledge royalties to federal and state governments and/or to certain charities. Additionally, an exclusive license may be in the public’s interest given that enabling one unified group to oversee the production of a vaccination will promote standardized quality control. In this regard, exclusive licensing of a vaccination is a reasonable and necessary incentive to attract investments of risk capital. These concerns need to be weighed against whether an exclusive license by any entity, whether a federal agency or a private company, is the best way to achieve this objective.

Elvina Chow is an LLM candidate at Stanford Law School and a student fellow at the Center for Law and the Biosciences.

Mini-Podcast with Carl Elliot

Mini-Podcast with Alta Charo

Mini-Podcast with Nita Farahany