Drug-Patent Abuse and the High Cost of Healthcare: Case of the Double-Half Dose-Time Injection

By Arie Michelsohn
March 20, 2018

Drug-Patent Abuse and the High Cost of Healthcare: Case of the Double-Half Dose-Time InjectionWhen true innovation is disclosed in the pages of a patent application, the innovator is rightfully granted a patent to secure what is presumably some inventive leap forward. While that may often be the case with first-generation pharmaceutical patents, follow-on patents covering blockbuster drugs more-often exhibit substantially less genius.

As a first example, consider the Humira patents.  Humira was first approved by the FDA in 2002, and the first Humira patent expired in 2016.

AbbVie’s patent thicket for Humira (generally, adalimumab) includes several patents for which petitions to the PTAB were filed.  These include U.S. Patent No. 8,889,135 (“the ‘135 patent”), one of a family that issued from applications that issued late in Humira’s lifecycle, shortly before the original patent expired.  The alleged innovation disclosed and claimed in the ‘135 patent essentially reduces to this:  Treat arthritis by arm-injecting (“subcutaneously”) with twice as much Humira (40mg instead of 20mg), at half the frequency (every 13-14 days—i.e., two weeks—instead of weekly).

Had a claimed “invention” of that magnitude been applied-for in the software arts, there is little doubt the patent examiners handling such an application would have rejected the claims out of hand.

AbbVie managed to convince the drug-patent examiner, however, that at the time of the alleged invention (around 2000), one of ordinary skill in the art would have considered it unreasonable to expect the newly-claimed dosing regimen would work, without clinical proof supplied by AbbVie.  This was even though the prior art knew that a twice-as-long, half-as-often dosing regimen worked just-fine when administered by intravenous (IV) means; that a 20mg dose per week subcutaneously worked nearly as effectively as 40mg per week; and that the half-life for Humira is nearly two-weeks long (between 11.6 and 13.7 days), meaning that half of a 40mg dose still is circulating in a patient’s bloodstream for a time-range that overlaps the claimed time range.

Is it really impossible for one of skill in the art to reasonably predict that a subcutaneous injection wouldn’t work similarly to an intravenously-administered injection, and where 20mg of a 40mg dose remains after nearly two weeks?

The problem here seems to be that the patent examiners who work in the pharmaceutical arts (or at least some of them) apply much-closer to an FDA standard when assessing obviousness. The FDA might want clinical trials to make sure treatments are as effective subcutaneously as they are intravenously, but the Patent Office is supposed to apply a different standard. The Patent Office is supposed to be concerned with the advancement of innovation. The FDA is concerned with safety.

Ever since the Supreme Court decided KSR v. Teleflex, it has been appropriate to reject a patent claim because it was obvious to try. If twice the dose intravenously, half as often works, why wouldn’t the highly-educated person of skill in the art – who would hold an M.D. or Ph.D. level education with years of experience – not be tempted to try the same thing subcutaneously? And if they do try it and the results are as expected that should mean, under KSR, that the claimed invention is obvious. Somehow in the pharmaceutical arts KSR does not get applied that way.

With its issued claims drawn to a presumed-inventive, shot-in-the-arm treatment for arthritis, the ‘135 patent thus was armed to block biosimilar competition for years.

For all those who want to argue how expensive it can be when clinical trials fail – that may be true with truly-new compounds that revolutionize treatment of a disease. It is, however, not true when it comes to making exponentially smaller leaps of ingenuity in moving from one dosing regimen to another.  In that scenario, there is essentially no downside-risk to the drug company in conducting clinical trials for a new dosing regimen or formulation for an existing drug, just the potential upside of convincing the PTO to issue a term extension for drug-market exclusivity, for no good reason.

Fortunately, in May and July 2017, three different panels of the Patent Trial and Appeal Board (PTAB) (with five different Administrative Patent Judges between them), saw through this charade.  Armed with the benefit of evidence from experts on both sides of the issue through trial, they agreed with the petitioners that the prior art already knew how to correlate IV dosing regimens to the more convenient arm-shot method, routinely; that a 20 mg dose per week was “nearly equally efficacious when given weekly via arm-injection (subcutaneously); and that the half-life for Humira is between 11.6 and 13.7 days; or at least that it would have been on any skilled doctor’s very-short list of obvious things to try a double-dose, half-as-often regimen, with a reasonable expectation that it would succeed at treating arthritis.  The patent was held to be invalid as obvious over the prior art.

The ‘135 patent does not appear to represent the kind of “innovation” or “invention” we should incentivize with a multi-billion-dollar annual bounty for the patentee, paid from the pockets of patients. And while it may be tempting to believe there is no real harm because insurance companies pay the bills, the undeniable truth is that one of the primary drivers for out-of-control medical insurance costs in America is the astronomical cost of drugs. So in the end, patients either pay themselves directly or indirectly through rising insurance premiums.

In the next installment, I will discuss another AbbVie blockbuster drug, which has been the subject of antitrust enforcement grounded in the exploitation of a major loophole in the drug-patent system arising from the listing of a drug patent in the so-called “Orange Book.”

The Author

Arie Michelsohn

Arie Michelsohn consults as counsel in patent law and litigation and related antitrust, and is Founding Principal of LexLaw.Consulting. He founded Lion Legal Products, a legal technology company based in Washington, D.C., in 2013, and has developed LexLab.io, a browser-based, total work space environment for lawyers, on a new platform called LEO. Arie is committed to the melding of law practice and computer science in the generation of what some have called "Centaur Lawyers." We like to think about it as the integral development of uniquely lawyer-driven, technology solutions to optimize efficiency in a manner that is tuned to the ways lawyers think, and work in their actual practice of law. Arie is a Caltech PhD, Order of the Coif graduate of the George Washington University Law School, a former patent examiner at the U.S. Patent & Trademark Office, and a former law clerk to the Honorable Raymond C. Clevenger, III, of the U.S. Court of Appeals for the Federal Circuit.

Warning & Disclaimer: The pages, articles and comments on IPWatchdog.com do not constitute legal advice, nor do they create any attorney-client relationship. The articles published express the personal opinion and views of the author and should not be attributed to the author’s employer, clients or the sponsors of IPWatchdog.com. Read more.

Discuss this

There are currently 15 Comments comments. Join the discussion.

  1. Josh Malone March 20, 2018 9:42 am

    Stipulating that it is obvious to one of ordinary skill under 103.

    It is a minor issue, which should be addressed by improving examination. If dosing regimens are not patentable, then there must be a precedential case and simple MPEP procedure to fix this.

    In the meantime, Doctors and Crohn’s sufferers can rejoice that they have at least two options for treatment – off patent IV, or the potentially more convenient Humira injections.

    Not only that, there will be more affordable injection treatments in 3 years when the injectable version goes off patent.

    Not only that, Humira’s patents, even the invalid ones, are encouraging their competitors to come up with better and cheaper alternative treatments – perhaps even a cure!

    Finally, if Humira truly has discovered a wonder drug and is holding up prices for 5 years longer than the law allows, then Coherus could explain that to a jury and ask them to release the treatment to the public by invalidating the patent.

    (Note that none of these responses involve commissioning a political agency to wipe out property rights by circumventing due process and jury trials.)

  2. Josh Malone March 20, 2018 9:45 am

    Got a little ahead of myself. Readers note that Humira is the name of drug. I should have referred to the manufacturer as AbbVie in my comment above.

  3. Anon March 20, 2018 9:50 am

    Very first sentence contains an inaccuracy.

    The notion of “leap forward” is NOT the only reason for the patent system.

    Leastwise, not directly.

    This comes from two different angles.

    The first is innovation itself, as anyone familiar with innovation theory can attest, some types of innovation (and mostly the ground-breaking kind) actually result in a short term retrograde movement.

    The second is in the nature of the patent system itself, and the multiple meanings of the word “promote.”

    One meaning (of course) is the advancement meaning. Such is not the only meaning of that word in the patent context. Another meaning of the word in the patent context aligns more with the sense of advertising: promotion.

    Those that have delved into innovation theory can also recognize why this is so: innovation will often come from not just the shoulders of giants before, but also from the toes of cross-fertilization. Promotion of any alternative modes in one art may very well provide the “A Ha” in other seemingly unrelated arts.

    There was a British television show called “Connections” that ably demonstrated this concept (James Burke: 1978).

    The use of the phrase “true innovation” must capture these notions.

  4. Anon March 20, 2018 10:01 am

    Mr. Malone also alights upon an idea that has been twisted to its opposite meaning in the eyes of the “popular press” and the Court.

    Blocking – as may come from the limited times of a granted patent – is practically always viewed as a de facto negative and bad thing.

    The plain truth is that this is NOT the case.

    The plain truth is that a strong patent system uses both a carrot approach and a stick approach.

    The closest maxim that applies:

    Necessity is the mother of invention

    It is when blocked and one chooses not to “pay the toll,” that is when the stick of innovation protection provides the impetus to creativity and innovation.

    Instead of duly celebrating this effect (and in its embrace, teaching how innovation in overcoming such obstacles truly advances the arts as the patent system provides), the anti-patentists whine that their desired copying is frustrated.

    Another maxim fits the indulgences granted to any such whining: spare the rod and spoil the child.

  5. Anon2 March 20, 2018 12:18 pm

    Anon@4

    You raise good points but you do not bother to address the presupposed narrative which is used to justify the supposed “rage” at the profits of pharma.

    This says it all from the article:

    “The ‘135 patent does not appear to represent the kind of “innovation” or “invention” we should incentivize with a multi-billion-dollar annual bounty for the patentee, paid from the pockets of patients. And while it may be tempting to believe there is no real harm because insurance companies pay the bills, the undeniable truth is that one of the primary drivers for out-of-control medical insurance costs in America is the astronomical cost of drugs. So in the end, patients either pay themselves directly or indirectly through rising insurance premiums.”

    The terms “bounty”, “pockets”, “harm”, “out-of-control”, “astronomical” are used as if they were factual and indisputable. This of course rests on “social” presuppositions which are assumed to be self-evident:

    “Social justice” implies that “Need” creates entitlement, entitlements being “claims” to a thing because it is needed and needed by those who cannot produce it. “Social Justice” therefore imposes upon “Property” in the inventions and in the production of those things to be “balanced” (if not overridden) by the entitlement/need i.e. the ownership by the producer to the inventions and the things produced is “partial”, the rights to the fruits of their mental and physical effort “moderated” by the “just” society. Those who produce (invent and manufacture) and attempt to charge the greatest which the market can bear (i.e. the NON-artificial price attached to the actual value of what they are providing) are thus adjudged as acting socially “unjustly”. The unfair position which their innovation and ability has afforded them, that they are first (perhaps the only ones) in a position to offer what is most greatly needed, and that they have secured property rights in it because they invented it, stands against them from a social justice perspective, undermining the very legitimacy of the rights to “property” in what they created… The more important the creation, the greater the demand and need, the less they should own. Thus the outrage, that anyone should attempt to profit in proportion to the value provided and the need being met, such would be improperly unmoderated and unjust given the need for drugs.

    From there it simply follows, the references to “bounty”, “pockets”, “harm”, “out-of-control”, and “astronomical”, are merely self-evident. Justice here does not consist of protection of individual rights but of redistribution of both rights and property, from those of ability to those of need.

  6. Anon March 20, 2018 1:29 pm

    Made it to the second sentence of the article only to find yet another flaw (which may submarine the author’s viewpoint):

    A lot of, some, or even a little of “genius” was explicitly rejected by Congress in reacting to the “thumb on the scale” (or if one prefers, the “fingers in the wax nose”) of the Supreme Court and the patent system.

    If the author is “aiming for” the law as written by Congress (or any disparate application of such between art units), a critical first step would be to show understanding of that law.

    Instead, I am left with the feeling that the author is attempting to insert a value judgment based on how that person would want the law to be.

  7. Anon March 20, 2018 1:31 pm

    Anon2 @5,

    My apologies, as I have not yet made it that deeply into the article.

  8. Anon March 20, 2018 5:15 pm

    THird item for me:

    The problem here seems to be that the patent examiners who work in the pharmaceutical arts (or at least some of them) apply much-closer to an FDA standard when assessing obviousness. The FDA might want clinical trials to make sure treatments are as effective subcutaneously as they are intravenously, but the Patent Office is supposed to apply a different standard.

    On what basis is this statement made?

  9. Anon March 20, 2018 5:18 pm

    Anon2,

    Your post does cap it off – such a heavy does of rhetoric actually works against the view that Mr. Michelson wants to advance (I am reminded of Shakespeare’s “the lady doth protest too much, methinks”).

  10. Anon2 March 21, 2018 9:11 am

    Anon@9

    The supposed proponents of patent rights, free markets, and individual rights, the so called classical liberalists are for the most part very disappointing in their failures intellectually and on principle, whenever the subject of medical/health goods and services are discussed. At least the Leftists are consistent in this regard, these liberalists talk out both sides of their mouths without even being aware of the obvious contradictions of what is said from the right and spewed from the left.

    No one seems to care that they are applying a double standard (of varying degree) when it comes to medical/health goods and services versus every other human endeavor. Of these persons I would have expected more.

    Generally speaking, self-identified supporters of capitalism and free markets are decidedly not innocent of this duplicity. They shrug as if to say, “yeah, I believe in free markets but morally drugs should be cheaper because, well people DO need them… I mean, how could I argue against that? and the high prices are artificial because … well it doesn’t matter , reason has its limits, no?”….One can almost imagine literally seeing the gears of reason grinding to a halt and the formless gibbering subliminal infant zombie of “feeling” taking over… At hearing only a handful of words they are helpless to the swift crumbling of their supposed stalwart support for the principles of individual rights. They are transformed directly as if by some dark and mysterious magic into a kind of mindless socialist and welfare-statist, bereft of reason and oblivious to reason’s necessity whenever the conversation turns to life saving drugs, or any poor soul who could not afford them, or any producer who profited handsomely from their sale.

    If these so called proponents of individual rights and free markets would put money where their mouths are they would stand against any claim that “Need” of any kind creates ANY entitlement to, claim to, or restraint upon property and freedom within the medical/health industry.

    Unfortunately the duplicity and the irrationality of this dichotomy is likely deeply subconscious, the hapless self-identified “classical liberalist” is unwittingly and in actuality, (whether due to culture, philosophy, religion, or sentiment swimming beneath their consciousness) quite simply Statist when it comes to healthcare.

    A “classical liberalist” suffering from this psychological and intellectual duplicity, if he/she has any intellectual honesty, should at the very least advocate for free markets and property rights, which do not unfairly target or single out the medical/healthcare industry, in order that it might flourish naturally, and THEN he/she can try to justify redistribution of wealth (after the fact) through general income or consumption taxes in order to support those in need, and in accord with their “entitlement” to life saving drugs. He/she should then with utmost dispatch disavow any self delusion that he/she is a classical liberalist.

  11. Anon March 21, 2018 9:57 am

    Anon2 @ 10,

    Bravo. Truly sublime.

  12. Greg Zornetzer March 21, 2018 9:05 pm

    The cited ‘135 patent only covers administration methods, so infringers would be either healthcare providers or patients, with producers potentially contributing to infringement. Although challenging at the PTAB was likely the easiest option for accessing the market, it probably wasn’t the only one available to challengers.

    I think that this discussion would benefit from more information about Humira’s larger patent family and administration methods in use at time of filing, which I’ve not researched. Distilling down the meat of a patent to a single sentence (as the author has done) runs the risk of over-simplifying the issue. The author notes that prior art methods included IV administration and subcutaneous (subq) administration at a lower dose. If the active lifetime >2 weeks and tolerated dosage level were known, the 2-week dosing window should have been obvious to try. If prior-art antibody therapies were effective with subq administration, then this administration route would likewise have been obvious to try.

    As mentioned by Mr. Malone above, if it’s a 103 issue, then prosecution should have caught it. If there’s systemic problem with biotech patent examiners not asserting 103, then it should be discussed and addressed. Clearly the author feels this is the case. I doubt it – the examiner on my applications (protein-based but not antibody) is good at coming up with rejections. Abbvie may have some very smart scientists, clinicians, and lawyers who managed to carve out a small but useful space for themselves. I’d like to see more examples from the author.

    I do echo the author’s point that the PTO and FDA have different goals – the FDA wants proof that the drug works as administered. Many drug treatments variants that are obvious to try will fail to show efficacy in the clinic. A positive clinical trial isn’t necessarily an indicator of innovation for the PTO.

    As a scientist, I’d like to see more discussion and analysis on the facts of this and other pharma patents. I’ll see what I can find.

  13. Anon March 21, 2018 10:15 pm

    I do echo the author’s point that the PTO and FDA have different goals – the FDA wants proof that the drug works as administered. Many drug treatments variants that are obvious to try will fail to show efficacy in the clinic. A positive clinical trial isn’t necessarily an indicator of innovation for the PTO.

    I am curious if this scientist recognizes the possession requirement of patent law (and yes, possession of a safe item is what is needed to satisfy the utility requirement in patent law).

  14. Greg Zornetzer March 22, 2018 2:59 pm

    Anon@13:
    If you’re referring to 35 US 112, yes, I recognize it. I’m not arguing possession. I’m making a comment on 35 USC 103 – obviousness. A lack of possession does not imply non-obviousness.
    My argument in this particular case is that a higher concentration might have been obvious to try (generating an objection under 35 USC 103, according to MPEP 2143) based on prior art known as of filing.

    More generally, a pharma may initially decide initiate clinical trials on a treatment with a larger patient pool or a higher probability of success. Additional studies might address other indications or different methods of administration. If those additional studies were obvious to try based on the available data, then no patent should be granted based on the outcome of those studies.

    Humira blocks inflammatory signalling and has been shown to work in Crohn’s, an autoinflammatory disease. It makes sense for Abbvie to run clinical trials on other autoinflammatory diseases, such as Blau’s syndrome, where TNF disruption is suggested to help. However, if an application is filed on those results, it should be carefully examined and challenged for obviousness. It would be obvious to treat autoinflammatory diseases with a drug that has already shown efficacy in one autoinflammatory disease. This should be the case even if Abbvie had not previously tested Humira on the disease.
    If someone discovers that Humira cures baldness, that’s likely non-obvious and would be deserving of additional patent protection on that use case.

    It seems that Abbvie has generated quite the arsenal of patents around Humira. It’s a smart strategy as long as enough of the patents survive court challenge.

  15. Anon March 22, 2018 4:35 pm

    Greg,

    My comment not only impinges on the possession of 112, but also the notion that the utility at time of filing (a 101 item) must also be possessed.

    If Big Pharma is filing prematurely, then their patents based on some eventual FDA testing show that they did not possess the required utility at the filing date.

    But “shhhhh” – Pharma gets a pass because “health” (or some such).

Post a Comment

Respectfully add to the discussion.

Name *
Email *
Website

Our website uses cookies to provide you with a better experience. Read our privacy policy for more information.Accept and Close