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The FDA Drops an Anvil on 23andMe – Now What? (slightly revised Wed. night)

On Friday, November 22, the FDA sent a nastygram to 23andMe, the only remaining substantial pillar of the “direct to consumer” (DTC) genomic testing industry. The letter, available here, is well worth reading in its entirety, but, in brief, it told 23andMe, in no uncertain terms, to stop marketing its “Saliva Collection Kit and Personal Genome Service” (“the PGS”) on the ground that it was an unapproved and uncleared “device” under the Federal Food, Drug, and Cosmetics Act.  It noted that the PGS, because of its lack of approval or clearance, was both adulterated and misbranded under the Act; the distribution of adulterated or misbranded devices is a federal crime.

23andMe’s initial response, click here, through an unnamed press spokesperson on its blog, was, at least on its face, conciliatory.

We have received the warning letter from the Food and Drug Administration. We recognize that we have not met the FDA’s expectations regarding timeline and communication regarding our submission. Our relationship with the FDA is extremely important to us and we are committed to fully engaging with them to address their concerns.

What’s going on – and what does it mean in the long run?

Read the rest of this entry »

Big Changes in the Works for Generic Drug Labeling

On Friday, FDA announced a proposed rule* that, if finalized, will represent a significant change for generic drug companies.  Section 505(j) of the Federal Food, Drug, and Cosmetic Act (FDCA) requires that, to be approved, generic drugs have the “same”** approved labeling as the brand-name drug (known as the reference listed drug, or RLD), and it has long been FDA’s position that this “same labeling” requirement applies throughout the life of the drug.  But the proposed rule announced Friday would change that position by allowing generic drug companies to substantively update their drugs’ labeling, without waiting for the RLD’s labeling to be updated first, to reflect newly acquired information about the drug.  This is big news not just because it would change generic drug companies’ obligations under FDA regulations, but also because of what this change may mean for generic drug companies’ tort liability. Read the rest of this entry »

OK S Ct Answers US S Ct's Questions in Cline v. OK Coalition for Reproductive Justice

in a way that I think means the S Ct will dismiss the case as improvidently granted.

Here’s the Oklahoma order, just out today: order.

Basically, the Court (7 justices concurring in the per curiam, two “not voting” – what’s with that?) held that when the Oklahoma statute required that all “abortion-inducing drugs” be used only according to FDA-approved protocols, the proper statutory construction meant that it included all three drugs that same statute had defined as “abortion-inducing drugs”:  RU-486 (mifepristone), misoprostol, and methetrexate.  The problem is that the FDA approved protocol for using mifepristone requires the use of misoprostol as a second drug. But the FDA approved protocol for using misoprostol does not include its use in causing abortions.

Read the rest of this entry »

The Journal of Law and the Biosciences Is Launched!

The Journal of Law and Biosciences is a peer-reviewed, faculty-edited journal published by Oxford University Press. It will publish three issues a year (in March, July, and November), on-line, on all areas of the intersection of law and the biosciences, from patent law and FDA regulation to cognitive enhancement and genetic selection, with many stops between. The Journal is owned by Duke University, Harvard Law School, and Stanford University.  Its founding three co-editors-in-chief are Nita Farahany at Duke, I. Glenn Cohen at Harvard, and me.  We’re looking for a few good papers of up to 10,000 words.  The Journal will also have a student-written “developments” section.  The Journal is now accepting submissions; here’s the link.

Hank Greely

"Electroceutical" Ads Are Here. What Will Regulators Say?

Post by Roland Nadler

Next time you impulsively pull up YouTube to check out the adorable cat video du jour, you might find your fix delayed by a most unusual advertisement:


Read the rest of this entry »

BioSci Fi: Childhood’s End, Arthur C. Clarke, 1953

About a year ago, this blog started a series on “bioscience” fiction:  series  intro.  That series has, thus far, comprised one post, on Robert Heinlein’s short story, Jerry Was a Man (here).  There has been no second.  Until now.

One night earlier this month I just couldn’t face the philosophy book I was trying to use as bedtime reading and wandered over to my science fiction bookcase for something lighter.  My eye fell on Childhood’s End.  My Ballantine Book’s paperback copy (which cost me 75 big cents at the time) is from the 15th printing, in 1970.  I probably hadn’t read the book since then, but I’ve remembered it warmly – really interesting plot and one great line.  Forty-some years later – and 60 years after it was first published – it stands up well, although not entirely as I remember it.

Read the rest of this entry »

Video: Brains on Trial: A Panel Discussion Moderated by Alan Alda

For those of you who missed our Brains on Trial event on October 2nd, video of the panel discussion is now available on YouTube.  The panelists were Silvia Bunge, Hank Greely, Robert Sapolsky, and Anthony Wagner, and the discussion was moderated by Alan Alda.  Check out their interesting discussion of various law and neuroscience issues!

CLB Podcast: October 2013

Hey CLB Podcast Listeners: Our new October 2013 podcast is up!  In this edition, we discuss the law enforcement purposes exception to the Genetic Information Nondiscrimination Act (GINA); the risk of liver injury associated with acetaminophen and FDA regulation of the drug, and; concussions and the future of football.  Enjoy!

U.S. v. Harkonen: Should Scientists Worry About Being Prosecuted for How They Interpret Their Research Results?

U.S. v. Harkonen — a case in which Dr. Scott Harkonen, former CEO of InterMune, was convicted of wire fraud based on a press release that discussed clinical trial results for one of InterMune’s drugs – has caused concern that Dr. Harkonen’s conviction means scientists could be subject to prosecution for (mis)interpreting their research results (see here, here, and here).  Dr. Harkonen and others who have voiced these concerns make compelling points—specifically, that scientific debate about the interpretation of research results is commonplace, this debate is critical for medical research, and it must not be chilled.  But are they right to argue that, if the Supreme Court declines to grant Dr. Harkonen’s petition for cert or otherwise allows his conviction to stand, Dr. Harkonen’s conviction puts such scientific debate at risk?  I think the answer is, probably, “no.” Read the rest of this entry »

SCOTUS Bioscience Cert Watch!

OT 2012 in the Supreme Court featured a total of five (maybe, five-and-a-half) bioscience cases: Bowman v. Monsanto (seed patenting); Mutual Pharma v. Bartlett (generic drug tort liability); FTC v. Actavis (pay-to-delay drug settlements); Maryland v. King(DNA collection of arrestees); and AMP v. Myriad Genetics (gene patenting). You can hear CLB’s podcast wrap-up of those decisions here.

But as Autumn comes and the leaves turn and Fall–well, in places other than evergreen Stanford, California–the Supreme Court is busy working on a new list of cases to hear for OT 2013. (At least until Friday, when it runs out of money.) And so–even though it’s ridiculously early to start counting these things–we thought it would be a good feature for CLB to update you on any bioscience cases the Court is slated to hear this term. All (maybe) three of them:

On. Oct. 16, the Court will hear Kansas v. Cheever, a criminal case slated to address whether a defense that focused on the neurological effects of the defendant’s habitual methamphetamine use counted as a “mental disease or defect” that allowed the trial court to order a psychiatric evaluation, otherwise in contravention of the Fifth Amendment’s protection against self incrimination. In other words–does, as a legal matter, smokin’ dat ice make you insane in the membrane?

On Nov. 12, the Court will hear a criminal case, Burrage v. United States, on whether one can be convicted for “distributing heroin causing death,” under 21 U.S.C. § 841,  if the cause of death was listed as “mixed drug intoxication.” This may seem like a run-of-the-mill criminal procedure issue on just how “proximate,” i.e., reasonably foreseeable, proximate cause needs to be. But, as noted by the government, the coroner’s report in the underlying criminal trial focused on the particular pharmacologic breakdown of heroin in the victim’s bloodstream. See Gov’t Br. at 4. If the coroner was wrong–or if the coroner’s opinion was uncertain–that may favor the petitioner-defendant. Frankly, it’s unclear how much this will play into the Court’s decision, but it’s something to watch out for.

Date uncertain: Cline v. Oklahoma Coalition for Reproductive Justice, on whether a state statute can condition the use of an abortifacient on-label, even if typical medical practice is to use it off-label, is still winding its way through the Oklahoma Supreme Court. Hank’s post about that case can be found here–with a correction here.

That’s it so far! We’ll keep you posted. You know, if the Supreme Court can get paid and get back to work any time soon.

Jacob S. Sherkow

Supreme Court Bioscience Wrap-Up Podcast

Hey CLB Podcast listeners: we’ve yet another podcast up for August 2013. Here, Hank and I wrap-up the five bioscience cases from the past Supreme Court term: Bowman v. Monsanto (seed patenting); Mutual Pharma v. Bartlett (generic drug tort liability); FTC v. Actavis (pay-to-delay drug settlements); Maryland v. King (DNA collection of arrestees); and AMP v. Myriad Genetics.


Jake Sherkow

Breaking News – FDA Issues Final Guidance on Mobile Medical Applications

Today FDA issued a final guidance document describing its policy on regulating mobile medical applications, an issue in which there has been a great deal of interest from Congress, industry, and the public (see, e.g., here and here). Read the rest of this entry »

CLB Podcast! August 2013

Hey CLB Podcast listeners: we’ve got our new podcast up for August 2013. In this edition, we welcome our new fellow, Patti Zettler, discuss whether blood is “property” for purposes of the federal rules, rehash Haskell v. Harris, talk about getting high–legally–in New Zealand, and knock-down the research egg-donation ban in California. Enjoy!

The California Aftermaths of Maryland v. King, Revisited

In June, after the U.S. Supreme Court decision in Maryland v. King on the constitutionality of mandatory collection of DNA from arrestees, I posted a long entry on how that case might, in ways more complicated that immediately obvious, play out in ongoing litigation about California’s statute.  Sequels.  Then I made a small post when the Ninth Circuit ordered supplemental briefing of its en banc case on this topic, Haskell v. HarrisAftermath Begins.  And one more on a particularly odd California trial court case affected by the decision.  Farce

Today, two weeks after receiving the last of the supplemental briefs,  the Ninth Circuit ordered a re-argument of the Haskell case before the en banc court on December 9.  Reargument.

This should be interesting!

By the way, on July 10, 2013, the California Supreme Court sent the state court case, People v. Buza, back to the intermediate appellate court for reconsideration in light of Maryland v. King:  “The above-entitled matter is transferred to the Court of Appeal, First Appellate District, Division Two, with directions to vacate its decision and to reconsider the cause in light of Maryland v. King (2013) __ U.S. __ [133 S.Ct. 1958, 186 L.Ed.2d 1]”

Hank Greely

Breaking News – CAFC Reverses Dt Ct Decision Not To Issue a Preliminary Injunction to Sequenom in an NIPT Patent Case

Friday afternoon, August 9, 2013, the Court of Appeals for the Federal Circuit, the appellate court for all patent cases, reversed an important patent decision by Judge Susan Y. Illston of the Northern District of California.  The four companies that offer non-invasive prenatal genetic diagnosis in the United States (Sequenom, Ariosa, Verinata, and Natera) are all suing each other in that district court for patent infringement.  Judge Illston had denied Sequnom’s motion for a preliminary injunction, which would have prevented Ariosa from offering its service in the U.S. at least until the case was finally resolved at trial or by settlement.  She did so for a variety of reasons, including some that boded extremely poorly for Sequenom’s chances of succeeding on the merits.

The CAFC has now reversed, in a unanimous opinion written by Judge Rader and joined by Judges Dyk and Reyna.  (You can download that opinion here.)   They vacated the lower court’s decision and remanded it for Judge Illston to “try again.”  They did NOT order that issue a preliminary injunction, let alone issue one themselves.  They did “correct her” about almost every reason she gave for denying the preliminary injunction.  Although there are still a few arguments open to Ariosa (and Judge Illston), the chances that Sequenom will be granted a preliminary injunction just got a lot greater.

The court first disagreed with the way Judge Illston had construed Sequenom’s patent claims. This is important because the way she construed them, Sequenom’s chances of success on the merits were small.  They aren’t now.  The court said “Even under the ostensibly more relaxed standard, the district court erred in its claim construction. As a consequence, the district court erred in finding a substantial question of noninfringement.”

The claim had talked about paternally inherited DNA, when the actual method looks at DNA inherited from both parents.  The lower court said the claim was limited to things that only found DNA known in advance to be paternally inherited – i.e., to a method that would only “read” the paternal DNA. The CAFC disagreed.

“Properly understood, this sentence describes the method of isolating and identifying any paternal characteristics by comparison to maternal characteristics, hardly a limitation to only paternal characteristics known in advance.”

The lower court read the claim’s discussion of “amplifying” as referring to amplifying only paternally inherited DNA.  The CAFC again said the lower court was just plain wrong.

Although Judge Illston concluded that Sequenom did not have a high likelihood of prevailing on the merits, she went ahead to analyze the other factors involved in granting a preliminary injunction as if it did have such a high likelihood.  She concluded, on several points, that the equities even then would favor NOT granting the injunction.  The CAFC disagreed on every, or just about every, point.

Although I am not and do not claim to be a patent lawyer, and I suspect I am missing something, As far as I can tell, the CAFC left only one obvious and substantial issue on which Sequenom could lose:  the question of patent-eligible subject matter under Section 101. This is the issue the Supreme Court has recently ruled on, in the Myriad case most recently as to “products of nature” and in the Mayo v. Prometheus case a few years ago as to “laws of nature.”

“The district court also found there was a substantial question over whether the subject matter of the asserted claims was to eligible subject matter. J.A. 16-19. Since the district court’s decision, the Supreme Court decided Association for Molecular Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107 (2013) (Myriad), which held that product claims directed to isolated DNA segments were not eligible subject matter, but that product claims directed to synthetic cDNA were patent eligible. See id. at 2119-20. Because the district court did not have the benefit of Myriad and also in light of this court’s disagreement with the district court’s claim construction, this court remands for the district court to examine subject matter eligibility in the first instance.”

‘To be clear, this court offers no opinion as to whether there is or is not a substantial question regarding the subject matter eligibility of the asserted claims.”

Do Sequenom’s claims involve products or laws of nature?  Beats me, in part because I haven’t read the claims themselves and in part because I have very little idea of what the Supreme Court means by either phrase.

So, what does this mean?

Well, for starters, I think they are dancing in the streets in San Diego at Sequenom’s headquarters. Good news for them.  But what about for everyone else?

It’s clearly not good news for Ariosa, Natera, and Verinata, though just how bad it is won’t be clear  The companies all use somewhat different technologies and all have their own patents, which they say Sequenom is infringing.  It is way too early to know whether even if an injunction issues against Ariosa (which it may not), the same thing would happen to Natera or Verinata. And, of course, there are other firms providing the service in other countries who might enter the US market – I have no idea what their patent situation is.  Plus there are companies trying to enter  the field that use entirely different methods – CellScape, for example, is not trying to read cell free fetal DNA but to isolate whole, intact fetal cells.

As I said earlier, I am not a patent lawyer.  Apart from the (admittedly important) issue of the patent infringement, as a matter of policy I would prefer a situation without an effective patent monopoly.  If Sequenom, or anyone else, has a patent-enforced monopoly on providing NIPT in the US, the technology will be more expensive, will expand more slowly, will improve more slowly, and will help fewer women than if there is effective competition.  So I’m rooting against Sequenom on this one, as a matter of policy, though I don’t know enough to have a good opinion on the proper outcome as a matter of law.

For the last time in this post, I’ll repeat that I am not a patent lawyer.  I hope some of my readers are.  What do you think about this decision?

Hank Greely

An Update to a 2011 Post About Doctors Using Copyright to Stifle Web Criticism

In July 2011, I posted an item about a clever scheme to stifle criticism of health professionals.  Through the help of a firm called “Medical Justice,” doctors and others could get a form for patients to sign, effectively giving the professional the copyright in anything the patient published about the provider.  The provider, if unhappy with, say, a Yelp review, could then demand of Yelp that the review be pulled, as a copyright infringement. Here’s that post: “If an Outrage Is Clever Enough, Is It Still an Outrage? Or, Kudos to Boalt Hall and Santa Clara Law School.

My SLS colleague Paul Goldstein just pointed out to me the playing out of at least one use of this copyright assignment strategy – the patient fought back and the provider (in this case a dentist) has disappeared!  Here’s a story on it from Ars Technica; a summary follows.

In 2010, a man named Robert Lee went to Dr. Stacey Makhnevich, the “Classical Singer Dentist of New York”.  He signed a form she offered him, entitled “Mutual Agreement to Maintain Privacy”, which she had received from Medical Justice.  He ended up very unhappy with the services he received and posted a scathing review on Yelp.  Makhnevich’s staff then filed “take down” notices under the Digital Millenium Copyright Act.  Yelp took the review down.  The dentist’s staff then sent invoices to Lee, claiming copyright damages of $100 a day.

He got in touch with Public Citizen and, with the help of Paul Levy there, in November 2011 he sued both Medical Justice and Dr. Makhnevich.  Medical Justice folded one day after the suit was filed, saying they were “withdrawing” that form.  Now the dentist has disappeared.  Her lawyers went to court to seek permission to drop their representation of her, as she hadn’t been in contact with them for three months and they can’t find her.  A default judgment may loom.

So, apparently, an outrage can be too clever by half and still be an outrage.  And keep an eye open for “the classical singer dentist”of wherever.

A Few Revisions to my Post on Cline v. Oklahoma Coalition for Reproductive Justice

My thanks to a commenter who pointed out a few things about my July 4 post on Cline, found here, that deserve correction or further comment.

First, the Supreme Court apparently does not need to grant cert to certify questions to state courts.  There’s not exactly a lot of clear, written rules on this stuff, but apparently they have certified questions before without granting cert.  Furthermore, the language “Further proceedings in this case are reserved pending receipt of a response” are not unusual in orders where the Supreme Court certifies questions – possibly ubiquitous but at least common.

These points are important  because it makes it at least somewhat more likely the Court (or four of its members) really will decide the Oklahoma case.  After receiving the answers from the Oklahoma Supreme Court, the Court could dismiss as improvidently granted, affirm summarily, reverse summarily, or set the case for full briefing and hearing.  The information about the Court’s practice in certification cases makes me lower, somewhat, my guess about the odds of a DIG.

My commenter took issue with my statement that the Oklahoma court will, in light of the statutory language, inevitably say the act banned even the on-label use of mifepristol because it bans the use off-label use of mifepristone, which is necessary to the on-label use of mifepristol, as well as my statement that the Supreme Court posing the questions “recognized” that the statute was poorly drafted.

After looking again at the State’s reply to the plaintiffs’ response to the petition for certiorari (available through SCOTUS blog), i still would be quite surprised if the Oklahoma Supreme Court doesn’t take the statute at its word and say that its workings effectively ban on-label use of mifepristol.  The state makes a very good effort with arguments from the canons of statutory construction to say that such a silly reading of the statute should be avoided.  I think those pretty good arguments won’t work, though, against a statute whose express language – banning all uses of any abortifacients off-label and expressly calling mifepristone an abortifacient – compels such a result.  Besides, the rest of the statute could still be meaningful if the FDA changed the labeling indications for either drug.

So, “inevitable” was too strong – I (and all of you) should know that nothing is inevitable in judicial construction of statutes, cases, constitutions, etc.  But I still think the Oklahoma Supreme Court is highly likely to construe the statute to ban entirely an FDA approved drug.  That, it seems to me, means the statute will fall as an undue burden, and probably on DIG.  It is conceivable that the U.S. Supreme Court might vacate and remand to the Oklahoma Supreme Court on the ground that its very cursory opinion did not perform the analysis required by Casey,  On the other hand, the trial court was more thorough.

So I’d still bet on the Oklahoma Supreme Court decision not being reversed and probably being DIG’d, but I won’t give quite as high odds.

One last point on timing.  The Oklahoma court has set a briefing schedule that points to an October hearing on the certified questions.  The Oklahoma court probably needs to answer the Supreme Court’s questions no later than early January for this case to be briefed and argued in OT 2013.  It could, of course, DIG it or affirm or reverse summarily in OT 2013 as long as it gets the answers by June.

Myriad sues Ambry over BRCA Testing

According to Genome Web, Myriad, and the other relevant patent-holders, have filed suit in the U.S. District Court for the District of Utah against Ambry Genetics on the ground that Ambry’s announced BRCA1 and BRCA2 testing infringes the patents held by Myriad and others. (And here’s a newer, longer, very good Genome Web story.)

Myriad took an aggressive posture immediately after the Supreme Court decision, claiming that their more than 500 valid patent claims still provided get intellectual property protection for their  BRCA testing business.  Given that

1.  The Supreme Court has invalidated its composition of matter claims for BRCA,

2. The Court of Appeals for the Federal Circuit, following the Supreme Court’s decision in Mayo v Prometheus, earlier invalidated its process claims for the method of comparing its patent sequences with a patient’s sequences to make risk predictions, and

3.  Ambry’s tests use a sequencing method that does not seem to require that it make cDNA of the BRCA genes, as to which the Supreme Court upheld the patent claims,

it will be really interesting to see Myriad’s arguments on this infringement case.

I suppose that after their aggressive response to the Court decision, failure to sue might have opened them up to securities law violations.  And, of course, I have not seen the complaint or studied the (so far non-existent) details of this suit.  And I’m not a patent lawyer. So maybe they’ve got some good arguments.  It would surprise me. (But I’ve been surprised before.)

Hank Greely

Cline v. Oklahoma Coalition for Reproductive Justice: A Fascinating Supreme Court (Sort of) Abortion, FDA, and First Amendment Case

Just before recessing for the summer, the Supreme Court issued an unusual order in Cline v. Oklahoma Coalition for Reproductive Justice.  The Court’s order reads, in full:

The petition for a writ of certiorari is granted.

This Court, pursuant to the Revised Uniform Certification of Questions of Law Act, Okla. Stat., Tit. 20, §1601 et seq. (West 2002), respectfully certifies to the Supreme Court of Oklahoma the following question: Whether H.B. No. 1970, Section 1, Chapter 216, O.S.L. 2011 prohibits: (1) the use of misoprostol to induce abortions, including the use of misoprostol in conjunction with mifepristone according to a protocol approved by the Food and Drug Administration; and (2) the use of methotrexate to treat ectopic pregnancies.

Further proceedings in this case are reserved pending receipt of a response from the Supreme Court of Oklahoma.

The Supreme Court Background

First, what does this mean?  Well, federal courts often have to pass on the constitutionality of state laws, but sometimes the meaning of the state laws isn’t very clear.  Determining the meaning of a state law is something that, in general, the federal courts would rather leave to the courts of the relevant state.  After various troublesome cases in 1967 the National Conference of Commissioners on Uniform State Laws proposed a Uniform Certification of Questions of State Law Act, which, when adopted by a state, allow federal courts to certify questions to that state’s courts. Between that Act, and other methods, all the state courts except those in North Carolina and Missouri (no idea why) will accept certified questions from federal courts, including the U.S. Supreme Court.

To have the jurisdiction to ask the questions, the Supreme Court has to grant review of the case (grant “certiorari” or “cert” in its lingo).  So, in this case the Court wanted the Oklahoma Supreme Court to answer some questions, so it granted cert and asked its questions, but it made it clear that it was not committing itself to hear the case until it had heard the Oklahoma Court’s answers, which is why it reserved further proceedings (like briefing) until those answers arrived.

Background to the Case

That’s the process, but what is this case and what do the questions mean in its context?

In 2010 Oklahoma passed a statute that for the first time put special requirements on medical (drug-induced) abortions, different from those applying generally to all abortions.  These requirements were largely requirements for disclosures to women about the procedure.

In 2011 Oklahoma enacted amendments to the previous act that move from disclosure to prohibition, providing, in relevant part

No physician who provides RU-486 (mifepristone) or any abortion-inducing drug shall knowingly or recklessly fail to provide or prescribe the RU-486 (mifepristone) or any abortion-inducing drug according to the protocol tested and authorized by the U.S. Food and Drug Administration and as authorized in the drug label for the RU-486 (mifepristone) or any abortion-inducing drug.

As far as I can tell, the act is to be enforced by civil actions for damages, actual and punitive, that, under the statute, can be brought by the pregnant woman, her husband at the time of the abortion, or the fetus’s maternal grandparents.  Successful plaintiffs are entitled to attorneys fees.[1]

RU-486, or mifepristone, is the so-called abortion pill.  Developed in France, the FDA finally approved it in the U.S. in 2000, as a non-invasive alternative to a surgical abortion.  The drug was approved, as is always the case with the FDA, with an approved label, which set out the indications and methods of use for which the FDA had found the drug “safe and effective.”  The labeled indication was a pregnancy up to not more than 49 days (seven weeks) after the last menstrual period.  The woman was to take 600 milligrams of the drug at a health care facility, then return two days later to take a dose of misoprostol, which helps in the expulsion of the fetal remains.  Two weeks later, the label requires the woman to return to the facility, to check to ensure that the procedure succeeded.

In the following 13 years, doctors have developed other ways to use RU-486 for abortion, methods that have been approved by the American College of Obstetricians and Gynecologists and the World Health Organization. These reduce the dose of RU-486 from 600 mg to 200 mg, allow the woman to take the misoprostol at home instead of in the clinic, and expand the appropriate period for use of RU-486 from seven weeks after the last menstrual period to nine weeks.  In some cases, other variations from the labeled instructions have been used.

Such “off-label” use is a common aspect of the FDA’s regulation of drugs and medical devices, and one that is strongly defended by the American Medical Association as limiting the FDA’s “regulation of the practice of medicine.” In many cases, off-label use of FDA approved drugs is the standard of care, violation of which can lead to malpractice verdicts or professional discipline.

The Oklahoma statute did not ban any off-label use except for that of RU-486 and any other “abortion-inducing drug.”  (It defined “abortion-inducing drugs” to include specifically both misoprostol and another drug, methotrexate, when they are used for the purpose of inducing abortions.)

The plaintiffs sued to enjoin the statute, contending (almost certainly correctly) that this was passed for the purpose, and with the effect, of substantially curtailing women’s access to medical abortions, by cutting two weeks off their useful period and by requiring additional expensive and difficult trips to clinics. The trial court granted summary judgment in favor of the plaintiffs.

The Oklahoma Supreme Court affirmed, after a fashion. Its three-paragraph, unanimous per curiam decision says the case is controlled by the U.S. Supreme Court’s decision in Planned Parenthood v. Casey.  Most of the opinion is taken up with recitations, from federal and Oklahoma law, of the supremacy of federal law.  (The court even included, as an indented block quotation, the entire Supremacy Clause of the federal constitution.)    The “analysis” is limited to the following: “The challenged measure is facially unconstitutional pursuant to Casey, 505 U.S. 833. The mandate of Casey remains binding on this Court until and unless the United States Supreme Court holds to the contrary.”  That is, “don’t blame us!”

The state applied for cert, contending that its Supreme Court had misread Casey and had ignored the Court’s subsequent Carhart opinion.  It also contended that the decision raised a conflict of authority with a Sixth Circuit decision, upholding a similar but somewhat more limited Ohio Statute, Planned Parenthood Southeast Ohio Region v. DeWine, 696 F.3d 490 (2012).  The original plaintiffs opposed cert and the Court ended up certifying its two questions to the Oklahoma Supreme Court.

The Interesting Issues

I work in Law and the Biosciences.  I keep an eye on the abortion cases and occasionally teach them a bit, but I do not usually write about them.  I do follow closely, and teach, FDA law.  And I’ve had to learn more about the First Amendment and commercial, or professional speech.  This is an interesting case for several reasons.

First, from an FDA perspective, I cannot remember a state ever banning an off label use of a prescription drug before.  States generally trust doctors with prescribing authority – and the AMA and state medical associations work to ensure that.  Off-label prescription is a deeply entrenched part of American medicine. Frankly, I am not keen on it, but a combination of practical and political reasons makes me think it won’t change. It was therefore a shock to me to see a statute banning such use.  I asked around and no one else could think of an example.

The only vaguely similar example I could come up with is sports performance-enhancing drugs.  Congress (not a state) banned off-label uses of anabolic steroids and then, a few years later in 1990, moved those drugs to Schedule III of the controlled substances act (and thus effectively banned off label uses). It slid human growth hormone into the gap, basically replacing the words “anabolic steroids” with “human growth hormone” and criminalizing off label use of that drug.  But those are the only examples of limits on off-label use (apart from the federal Controlled Substances Act) that I can think of – and they are Congressional actions.

Having said that, I don’t really see a good federal preemption argument. Yes, the Federal Food Drug and Cosmetic Act allows off-label use.  And it authorizes on-label use to the extent that state laws restricting it may be preempted – see the Supreme Court cases  preempting state tort (or product liability) cases for devices or generic (but not brand name) drugs. But it seems to me hard to say that just because federal law permits doctors to prescribe a drug for uses that the federal government has never specifically approved, it therefore preempts states from forbidding those uses that the FDA has not specifically approved.

Second, as a matter of constitutional abortion laws, governments cannot impose “undue burdens” on the right to an abortion.  This seems to me a winner in this context. In light of the ACOG and WHO endorsement of the off-label regimens, it seems to me very hard to argue that demanding on-label use of RU-486 provides no significant benefits. It imposes more restrictive limits and more doctor visits on the women seeking abortions.  When the cost has no countervailing benefit it seems to me that imposes, by definition, an “undue” burden.

Two of three judges on the Sixth Circuit Planned Parenthood panel disagreed.  I think they erred by not measuring the “undue” or “due” nature of the burden in relation to the benefits of the regulation.  In any event, they did not decide the question whether the Act unduly burdens a woman’s right to health and life under the Fourteenth Amendment, which was held for trial at the district court.

Third, in an idea raised to me by a former CLB fellow, what about the First Amendment?  A doctor writes a prescription for the pills. Does what he says about how they should be taken – the dose, the location, the timing – fall within First Amendment protections for speech with patients?  I am leery about the application of commercial speech to medicine – it seems to me it could undue much valuable regulation.  But the courts do not necessarily share my views. Late last year, in a heralded case, U.S. v. Caronia, the Second Circuit reversed a criminal conviction for off-label promotion of a date rape drug on the ground that it punished the drug rep for speaking. The court analyzed the restriction under the Commercial Free Speech factors of Central Hudson and found it constitutionally lacking.  I’m not happy about that decision, but, if it ends up being “the law,” how would that affect this case?

I would note a different First Amendment case I like better from Florida.  The Florida legislation forbid doctors from asking their patients about their ownership of guns (something doctors with depressed patients had an understandable interest in).  A federal district court enjoined that statute in Wollschlaeger v. Scott in July 2012 as a violation of the doctors’ (and patients’) First Amendment rights.  The appeal is pending in the 11th Circuit.

It does seem to me that “treating a patient” with a prescription drug is not just “speech,” but then, it seemed to me that banning pharmaceutical companies from getting access to physician prescription records that they wanted to use for marketing purposes wasn’t exactly speech, either. The Supreme Court disagreed, in Sorrell v. IMS Health Inc.  I don’t know much about the First Amendment’s application to professional speech; I don’t think I want to know much about it.  But it seems to me it might be applied here.

The Likely Resolution

In fact, though, I do not think the Oklahoma case is likely to be a vehicle to explore any of these issues.  As the plaintiffs argued, both in their complaint and in their opposition to the petition for certiorari – and as the Supreme Court’s questions recognize – the Oklahoma law was drafted poorly in a way that bans more than just off-label use of RU-486.

The Oklahoma statute requires on-label use only of all abortion-inducing drugs, including specifically misoprostol and methotrexate, when used for the purpose of inducing abortions.  This was, not to put too fine a point on it, dumb.

The FDA’s label for the use of RU-486 includes the use of misoprostol as part of the medical abortion.  But misoprostol’s label does not include its use as part of a surgical abortion. In fact, its only currently approved (and thus labeled) use is to prevent stomach ulcers in people taking non-steroidal anti-inflammatory drugs (like aspirin).  Its use with mifepristone is off-label (as is its quite common use in inducing labor).  The Oklahoma statute, by requiring only on-label use of RU-486, requires the use of misoprostol, but that same statute, by requiring only on-label use of misoprostol, forbids that use.  It thus bans all use of RU-486.  Similarly, methotrexate, originally approved as chemotherapy for an uncommon cancer, is the only drug available for medical use in ectopic pregnancy, a pregnancy where the fetus is attached to the fallopian tubes and not the uterus. That condition is fatal for the fetus and very dangerous for the woman. Medical treatment with methotrexate is safer than surgical removal – but that’s also off label and so forbidden in Oklahoma.

The Court noticed.  The questions it asks the Oklahoma court are whether the statute prohibits using misoprostol to induce abortions and prohibits use of methotrexate to treat ectopic pregnancies.  Assuming the Oklahoma court says that it does – which, from the statutory language, would seem inevitable – the act will clearly ban an FDA-approved method of medical abortion and ban a safer treatment for ectopic pregnancy, both of which would seem easily “undue burdens.”

Thus the Court seems highly likely, after getting such answers from the Oklahoma court, to dismiss the writ of certiorari and allowing the Oklahoma trial court’s injunction to stand . . . until Oklahoma next amends its statute.  There will be other chances – the Ohio case may eventually reach the Court and both North Dakota and Arizona have enacted laws similar to Ohio’s.  North Dakota’s statute is currently enjoined as litigation continues.


Cline v. Oklahoma Coalition for Reproductive Justice itself seems unlikely to make interesting or important law. But the anti-abortion strategy behind it, when embodied in more competently drafted statutes, may.  This is worth watching.

Hank Greely

[1] The plaintiffs’ complaint says it also subjects the physicians and any licensed facility where the procedures are performed to disciplinary sanctions; I don’t see that in the Act, except with respect to certain reporting requirements, but I suspect the plaintiffs’ lawyers are right.

Myriad Decision Invoked in Appeal of Suit To Invalidate Embryonic Stem Cell Patent Claims

On June 13, the U.S. Supreme Court struck down patent claims of Myriad Genetics to genomic DNA in the BRCA1 and BRCA2 genes on the ground that those patents claimed mere “products of nature.”  Only occasionally mentioned in the commentary on that decision was the possible extension of this decision from human genomic DNA to other naturally occurring biological substances, such as molecules or proteins.  (The CLB blog’s coverage, here, did mention that uncertainty.)

On July 2, the first step may have been taken toward such an extension of the Myriad rationale.  On that date, two public interest groups, Consumer Watchdog and the Public Patent Foundation, filed a brief with the Court of Appeals for the Federal Circuit in Consumer Watchdog v. Wisconsin Alumni Research Foundation.  In that brief, they argue that patent claims on human embryonic stem cells, held by the Wisconsin Alumni Research Foundation (WARF) are invalid under the Myriad decision because they are “products of nature.”  Here is their press release, here is their brief for download, and here is the Genome Web story about the brief.

The Public Patent Foundation filed the brief as counsel for Consumer Watchdog in an appeal from a “Decision on Appeal” of the Board of Patent Appeals and Interferences (now known as the Patent Trial Appeal Board) in an inter partes re-examination of certain patents.  On July 17, 2006, Consumer Watchdog had filed a request for inter partes re-examination of patent 7,029,913 (“the ‘913’ patent”) that had issued on April 18, 2006 to Professor James Thomson and been assigned to WARF.   Consumer Watchdog argued that three claims of the patent for in vitro cultures of human embryonic stem cell lines had been obvious in light of the prior art.  Any person of ordinary skill in the art of deriving and maintaining embryonic stem cell lines for any mammal would have found the process used to derive these human stem cell lines obvious or, at least, obvious to try.

The Examiner granted Consumer Watchdog’s request for re-examination but then held that the claims were allowable. The  Patent and Trademark Office Board first agreed with Consumer Watch that the claims were obvious and, on April 29, 2010, reversed the Examiner.  WARF filed a Request to Reopen Prosecution, with some amendments to the application, supported by new evidence.  The Examiner determined that these claims were patentable in spite of the earlier objections from the Board. On January 22, 2013, the Board affirmed the Examiner’s latest decision, leading to this appeal.

Most of the argument in the brief is directed to Consumer Watchdog’s earlier argument of obviousness, but the first four pages of the 17 pages of argument take up the Myriad issue.  The brief argues that the claims are only for “replicating in vitro cell culture[s] of pluripotent human embryonic stem cells derived from a pre-implantation embryo,” which have characteristics that the brief maintains all embryonic stem cells have. Thus, the brief urges, these are just “products of nature” and thus, following Myriad, not patentable subject matter  under Section 101.  Several of the those four pages are dedicated to arguing that the Federal Circuit should consider this argument even though it was not raised below.

Jake Sherkow’s June 13 blog post with his first thoughts on Myriad warned that among other questions, the decision left unanswered “What about other patents directed to “isolated and purified” natural products?”. Well, less than three weeks later, that very issue is being raised with another very high profile biological patent.

Of course, the Court of Appeals for the Federal Circuit may not resolve that question.  It may decide not to consider this issue because it was not raised below (even though Consumer Watchdog’s lawyers, the Public Patent Foundation, including Daniel Ravicher, also litigated the Myriad case).  It may decide not to consider the issue because it feels compelled to rule for the appellant on the obviousness claims.

And if does consider the issue, it may resolve it narrowly.  It seems to me quite plausible that human embryonic stem cells, grown in petri dishes in manufactured culture medium and in a man-made environment, are not the same thing as human embryonic stem cells inside a blastocyst (which are usually called inner cell mass cells and not embryonic stem cells). This is especially true as the cultured cells can be kept alive indefinitely without differentiating, something that does not happen in nature.

A stronger question would probably be one both Jake and I have written about – what about a biological molecule secreted, let’s say, by a fungus that a pharmaceutical company notices has therapeutic properties?  Consumer Watchdog v. WARF seems unlikely to resolve that question – but it does make clear that the Supreme Court’s Myriad opinion is going to spawn such questions.  That’s good for patent lawyers and patent law scholars. Whether it is good for anyone else remains to be seen.

Hank Greely