Prometheus v. Mayo – The Wrong Rat?

By Paul Cole
May 6, 2012

A decision with the right outcome but for the wrong reasons can confound jurisprudence nearly as much as a decision that is entirely wrong.

In our field an example is provided by the opinion of  Justice Douglas in Funk Brothers Seed v Kalo Inoculant, 333 US 127 (1948) which has recently been exhumed following decades of obscurity. The invention in that case concerned an inoculant for leguminous plants containing mutually non-inhibitive strains of Rhizobium bacteria. Modern readers would find it a surprising proposition that identifying such strains and enabling a farmer to conduct a single treatment of his fields when formerly six separate treatments were needed did not amount to invention. The rat which Justice Douglas smelled existed but was mischaracterised. As set out in the concurring opinion of Justice Frankfurter it was not enough to conceive of the idea that non-interfering strains might exist: it was necessary to go further and identify particular operable strains of bacteria (this was, of course, well before deposit systems for bacteria and other living species were established). The proper ground of non-enforceability was non-enablement, not obviousness.

Similarly in Mayo v. Prometheus the proper objection, it is submitted, was obviousness, not patent-eligibility. In its desire to issue a decisive opinion and to produce a correct outcome it is submitted that the court over-stretched the principles of patent-eligibility under 35 USC §101 and inadmissibly combined the §101 objection with §§102 and 103 objections, as suggested by commentators. To understand why the court may have been tempted to do so, it is necessary to consider the relevant factual background.

The thiopurine drugs were first used by Sir Roy Calne in Cambridge, England in the 1970’s to minimise transplant rejection. Subsequently they were suggested for use in the treatment of inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease in order to avoid or minimise the use of steroids.

The inventors of the patent in issue, Ernest Seidman and Yves Théorêt, worked at a hospital in Montreal and suggested a metabolite-based blood test which would facilitate safe administration of drugs in this family. Patient monitoring over a period to maintain metabolite levels within a safe range was needed, as the chart below from a brochure of the licensees Prometheus illustrates.

The advantages of the Prometheus test are explained in their merits brief to the Supreme Court:

The practical problem addressed by the patents-in suit is determining the proper thiopurine dose for each patient. Because of variations in the activity level of the enzyme that breaks down these drugs (thiopurine methyltransferase, or TPMT), everyone metabolizes thiopurines differently. If a dose turns out to be too high for a particular patient, it could cause severe, potentially fatal, side-effects. Even “minimal doses” can be fatal for a minority of the population. These risks typically led doctors who used thiopurines to start with a very low dose and work slowly upwards while continually monitoring and testing their patients’ blood and liver for toxicity. This “start low, go slow” approach multiplied office visits and costs and dramatically delayed the drug’s effectiveness. And doctors still risked toxic consequences if they overshot the appropriate dosage for a particular patient. Many physicians, accordingly, were reluctant to treat their patients with thiopurines despite the potential benefits.

Researchers appreciated, in theory, that determining a patient’s thiopurine metabolite levels could provide valuable information about the efficiency with which that patient metabolizes the drug. And laboratories had the technology to determine those metabolite levels from blood or bodily samples.  But developing and validating a metabolite-based treatment protocol proved difficult because the complex metabolic pathways at issue were not completely understood…

No evidence in this record supports Mayo’s suggestion that, when that application was filed, doctors were already using measured metabolite levels clinically to calibrate thiopurine dosages for patients suffering from autoimmune disorders. To the contrary, at the time, there was persistent skepticism about whether monitoring metabolite levels would improve patient treatment. In 1997, for example, Mayo’s own Dr. Sandborn wrote that “measurement of [red blood cell] 6-TGN and 6-MMP in patients with Crohn’s disease treated with AZA or 6-MP remains investigational and cannot be recommended for routine clinical use.” It was not until 1999, when Prometheus introduced its test, that metabolite measuring tests became commercially available to practicing gastroenterologists…

Since their introduction, Prometheus’s patented methods have improved the lives of countless individuals suffering from autoimmune diseases. With these tools, doctors are both more willing and better able to treat patients effectively with thiopurines and minimize resort to more toxic or less effective drugs.

Mayo’s case was that all that might have been true, but from the standpoint of patent law it is beside the point because it does not start from the most relevant prior art. In their brief they objected that the inventors had in 1996 and well before the patents were filed freely published in a paper in an academic journal the general association between thiopurine metabolites and the efficacy or toxicity of thiopurine therapy. In an act of obfuscation worthy of the fictional Sir Humphrey Appleby (BBC Television: Yes Minister) that paper is referred to not in the Background section but in the middle of a lengthy specific description with the result that although its existence had been disclosed to both examining authorities (thus inter alia satisfying US disclosure requirements) neither the US examiner nor his European counterpart was prompted to study it and appreciate its significance. The final paragraph of the 1996 paper explains:

Our recent preliminary investigative efforts to measure 6-TG in leucocytes has shown a correlation between neutrophil 6-TG levels and responsiveness to treatment as well as drug induced leucopenia. Further research is needed to identify a therapeutic regimen for 6-MP treatment allowing clinicians to establish a balance between drug responsiveness and toxicity.

It is difficult to avoid the conclusion that all that found its way into the Siedman patents was the results of the very research that had been recommended in the 1996 paper and which Prometheus had been prompted to under-write. The more natural objection which, unfortunately, was not pursued was therefore lack of inventive step under 35 USC §103. It is submitted that this should have been enough to dispose of the issue between the parties, arguably even in a motion for summary judgment, but unfortunately it was not how the case was pleaded and argued.

The temptation to pursue the §101 objection may have been strengthened by the idiosyncratic form of the allowed claim which read:

A method of optimizing therapeutic efficacy for treatment of an immune-mediated gastrointestinal disorder, comprising:

(a) administering a drug providing 6-thioguanine to a subject having said immune-mediated gastrointestinal disorder; and

(b) determining the level of 6-thioguanine in said subject having said immune-mediated gastrointestinal disorder,

wherein the level of 6-thioguanine less than about 230 pmol per 8×108 red blood cells indicates a need to increase the amount of said drug subsequently administered to said subject and

wherein the level of 6-thioguanine greater than about 400 pmol per 8×108 red blood cells indicates a need to decrease the amount of said drug.

As has been indicated in essence and in its practical embodiment the invention concerned a blood test. When blood is centrifuged, there is a layer of plasma, a thin layer of leucocytes (white blood cells) and platelets and a deep lower layer of erythrocytes (red blood cells). The practical embodiments of the test were carried out by analysing the red blood cells, and although cheek cells and white blood cells are mentioned in the specification, owing to their lower abundance and the desirability of simple procedure it is doubtful whether these alternatives are realistic. What was the most advantageous, therefore, was a straightforward claim to a blood test for determining metabolite level in red blood cells.

The word “optimising” gives rise to clarity issues given the lack of any specified post-determination human activity, although no issue appears to have been raised in that regard. The administration step presumably involves the doctor or pharmacist whereas the determination step will be carried out in a remote lab, so that infringement of the claim by a single entity is difficult to establish. The determination step invokes no corresponding structure and therefore is clearly a step + function limitation within 35 USC 112(6). Its scope is therefore narrower than appears on the face of the claim, although this point does not appear to have been a subject of discussion. Implicitly it appears to require a sample from the human body for analysis. The “wherein” clauses are foreseeably problematic under 35 USC 101 since they do not define process features, nor do they define a machine, manufacture or composition of matter.

The granted claim in the corresponding EP-B-1114403 (Seidman) which corresponds to US 6355623 is more straightforward and might have created less difficulty if the same wording had been employed in the US:

An in vitro method for determining efficacy of treatment of a subject having an immune-mediated gastrointestinal disorder or a non-inflammatory bowel disease (non-IBD) autoimmune disease by administration of a 6-mercaptopurine drug, comprising

determining in vitro a level of 6-thioguanine in a sample from said subject having said immune-mediated gastrointestinal disorder or said non-inflammatory bowel disease (non-IBD) autoimmune disease,

wherein said treatment is considered efficient if the level of 6-thioguanine is in the range of about 230 pmol per 8×108 red blood cells to about 400 pmol per 8×108 red blood cells.

An even simpler formulation might have been:

A method of testing whether a patient suffering from an immune-mediated gastrointestinal disorder is receiving a therapeutically effective dose of a drug providing 6-thioguanine whilst being at low risk of leucopenia, which comprises separating red blood cells from a sample from the patient and determining whether the level of 6-thioguanine is within the range 230 – 400 pmol per 8×108 red blood cells.

Such considerations are, however, moot bearing in mind the strength of the potential obviousness objection.  Why it was rejected by Mayo in preference to a patent eligibility objection must remain a matter of conjecture.

The Author

Paul Cole

Paul Cole

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 17 Comments comments.

  1. John Roethel May 6, 2012 11:55 pm

    I’m not a chemical guy, but:
    why did the claim not positively recite the adjustment step — when the level of X is less than Y, increasing the amount of drug to the patient, when the level of X is more than Y, decreasing the amount of drug to the patient…

    It seems §112ish to me that by using the wherein clause as drafted, the claim would be vague and indefinite as to whether the adjustment step is or is not part of the claimed invention.

    Is there a class of potential infringers that would not be liable if the claim positively recited the adjustment step? That would seem to be the only reason to me to fudge the adjustment step into a wherein clause.

  2. Paul Cole May 7, 2012 2:26 am

    Prometheus was a testing laboratory. They did not set the dose – it was the doctor who prescribed the blood test and then interpreted its results that did that. They did not wish to write a claim specifying the doctor. So they went no further than carrying out the test and reporting the results because that is just what they don.

    If they had made it into a method of medical treatment claim involving administering thiopurine, carrying out the test and then adjusting the dose in response to the test, the claim would have been less easy to attack under section 101 as method of medical treatment claims are allowable in the US. But it would have been harder to prove infringement. The person drafting the claim did not have an easy task.

  3. MuenchnenOst May 7, 2012 3:12 am

    Excellent post Paul but, looking at your claim, can you reassure me on its novelty?

    Specifically, I am supposing that the determining step is what you rely upon, to confer novelty, but does it really?

    Suppose those who were already performing the blood test got a result, expressed as a number of pmol. Further suppose that those folks looked with interest at the number their test delivered. So were they not also, albeit implicitly, inevitably performing your determining step?

    I’m imagining a Test report, in which the values 230 and 400 appear. Then I can see evidence of your determining step. But what if the Test Lab simply delivers a numerical result without embellishment, comment or annotation? Does that Lab infringe?

    I suppose it would help, to have infringement and validity decided at the same time, by a single judge, who then has to write a single coherent logical and just decision, that covers both validity and infringement.

  4. MuenchnenOst May 7, 2012 5:34 am

    Paul, I have just seen your Titanic contribution over on that other popular patent law blog, in the Frischmann thread. I appreciate your homage to those who enable novel, non-obvious and useful contributions to the totality of technical knowledge.

    There is still the difficulty, however, of devising for them an effective claim that’s valid. I wonder if your Titanic example bolsters my novelty point. Captain Smith did not know how many flooded compartments would sink his ship but, nevertheless, he had surely already “determined” whether the number of compartments getting flooded was between 230 and 400.

    Back in the early 1980’s, the Enlarged Board ratified use claims. Far-sighted, or what? There’s an example of a Supreme Court getting it right, in the face of howls of protest.

  5. EG May 7, 2012 8:14 am

    “why did the claim not positively recite the adjustment step — when the level of X is less than Y, increasing the amount of drug to the patient, when the level of X is more than Y, decreasing the amount of drug to the patient”

    John,

    That was done in a separate patent, as pointed out by Steve Hansen. See Claims 1 and 13 of U.S. Pat. No. 6,987,097. As Paul correctly points out, the problem is how to craft the claims so that the testing lab infringes. Given the result in the Prometheus case, that’s not that easy to do any more.

    As Paul also correctly points out, the problem with the Prometheus case is that the reasoning used to the support the result under 35 USC 101 is utter gibberish. SCOTUS can’t even use patent claim terminology correctly, so it’s no wonder the legal reasoning provided in the Prometheus case is a mess.

  6. step back May 7, 2012 8:43 am

    The world is full of apologists and denialists.

    MvP is an abomination. Period.

    There is no rational excuse for how the Supremes behaved.
    A rat is a rat.
    A patent hater is a hater.
    Period.

    The MvP opinion makes it clear that SCOTUS has no idea what they are talking about.
    The MvP opinion makes it clear that SCOTUS dislikes inventors and invention.

    They have no clue regarding what “science” is.
    They have no clue of how a patent is enforced.
    They have no clue how inventions and discoveries are arrived at.

    Nothing adds up to rational thinking in the MVP decision.
    All it does is subtract from the reputation of SCOTUS.

    I know we are taught in school to show great respect for SCOTUS.
    But sorry.
    They lost me in the “abstractness” of Bilski and the “common sense” of KSR.
    MvP is merely where they make their self-dug rat hole “naturally” wider and deeper.
    Stop apologizing for them.
    Stop denying their anathema for inventors and for securing exclusive rights for the same.

  7. Gee May 7, 2012 12:38 pm

    1. Abstract ideas and laws of nature are not patentable.

    2. “Inventions” which effectively monopolize all practical uses of an abstract idea of a law of nature are also not patentable. (The policy reasoning for this should be obvious.)

    2a. It does not matter if the scope of the abstract idea or natural law is narrow: “Inventions” which effectively monopolize all practical uses of an abstract idea of a law of nature, even where the idea or law is narrow in scope, are not patentable under 101.

    3. Regardless of any implication regarding 103 or 112 rejections, 101 stands on its own as a basis for rejection.

    (the above 1-3 are the holdings from Diamond v. Diehr and the patentability trilogy…, i.e. that’s what the law is.)

    Ergo: The holding in MvP is not confused. It is a direct application of Diamond v. Diehr. The invention in MvP effectively attempts to monopolize all practical uses of a natural law (albeit a law very narrow in scope). It is therefore unpatentable under 101. The basis for rejection under 101 is proper regardless of 103/112 because 101 stands on its own as a basis for rejection.

    I believe that it’s the patent bar and the Federal Circuit that are confused, because they have never recognized 2,2a above as the law (and will probably continue to fail to recognize it as the law).

    Practically speaking, I think commenter #1 is correct: you just need to add a little something to the claim get out of the 101 rejection – like a particular apparatus for monitoring the blood, or maybe a particular amount of drug to administer at each step. This takes the claim outside the scope of monopolizing the use of a natural law/relationship into a particular application thereof.

  8. Anon May 7, 2012 1:15 pm

    Gee,

    Maybe you should pay attention tot he actual case and how certain elements were hand waived away (in direct contradiction to your point 3).

    Your points on 2 and 2a lend themselves to vagueness and misapplication due to the uncertainty of the word “effectively.” It’s not that something that DOES monoplize ALL uses of an abstract idea or a law of nature is being questioned. And even that may be questioned because the leap of faith required to go from coverage to the thing itself is at least an arguable point. For example, Benson fell along the logic here, but it is quite easy to show that Benson was decided incorrectly as I am aware of at a least two uses that esapce teh Court’s too-inclusive pronouncement. The Suprmee Court has often chastised the CAFC for taking shortcuts. The Supreme Court, likewise, should be chastised when it takes shortcuts.

    Your point 1 is also debatable as to the ongoing discussion over who gets to set patent law. In a hypothetical, Congress tomorrow sets the law that laws of nature are patentable (because we really do want to have people like Einstein coming forward quicker with better laws of nature. The Supreme Court would be committing an unconstitutaionla act to take this power away from Congress.

    As to just who is confused betweenthe SUpreme Court and the CAFC, if you were to read the Prometheus decision objectively and carefully and actually look at teh previous decisions, you will without a doubt conclude that it is the Supreme Court that is confused. Prometheus simply cannot square with the very decisions that Breyer says he depends upon.

  9. step back May 7, 2012 1:16 pm

    Another apologist who won’t deal with the facts of the case (or the purpose of getting a patent, which is to yes, “effectively monopolize” that which is your inventive contribution to society).

  10. step back May 7, 2012 2:09 pm

    Anon, sorry our posts crossed within a minute of each other
    Mine was direct to Gee Whiz, but less eloquently than yours

    Just in case Gee Whiz is paying attention:

    1) There is no “Law of Nature” requiring administration of the subject drug to a patient suffering from the recited disease,
    2) There is no “Law of Nature” requiring extraction of a blood sample from the same patient and chemically analyzing that blood sample to “determine” the concentration of the specifically recited metabolite
    3) There is no fixed correlation between dosage swallowed and how each diseased individual metabolizes that drug

    4) A method claim is made out of specific steps
    In the MvP case those steps where a) physically administering the drug to the diseased patient and b) physically determining concentration of the specific metabolite

    Neither of those steps are required by any known “Law of Nature”

    SCOTUS does not know what they are talking about and neither do you.

  11. Stan E. Delo May 8, 2012 12:16 am

    Step back writes in part:
    “Nothing adds up to rational thinking in the MVP decision.
    All it does is subtract from the reputation of SCOTUS.”

    I once also had a great respect for the Supreme Court, which is an important part of the US form of government. To see them get something as important as patent rights all goofed up was a great disappointment for myself at least. It will probably take Congress about 10 years to revisit the *America Invents Act*, if they ever do at all. A glimmer of hope though, as I believe Kappos and et al might be producing a proposed Technical Amendment to the language of the AIA, which would be a great relief to nearly all of us.

    If Congress likes the proposal, and votes to to ratify it, it will become law. Keep your fingers crossed!

    SD~

  12. Paul Cole May 8, 2012 3:25 am

    I think that it is worth repeating the Titanic scenario because it could help non-chemists understand the underlying facts.

    Consider the situation on-board Titanic immediately after it hit the iceberg. The Ship’s carpenter and Captain Smith tested to see whether the ship was making water. They lowered probes into several compartments and measured the height to which the probes were wetted. But they did not know whether or not the ship would sink. Thomas Andrews was the designer, had done the necessary calculations and may have made models. He knew that if four or less compartments were flooding the ship would continue to float and with five or more compartments flooding it would sink. With that knowledge he was able to tell Captain Smith that the ship would indeed sink quite soon and that lifeboats should be launched. Whatever was the loss of life on Titanic, it would have been greater without that knowledge because launch of lifeboats would have been delayed.

    Prior to the patent in issue the state of knowledge was analogous to the ship’s carpenter or Captain Smith – they could do tests but did not know how to interpret them. With the further information in the patent the level of knowledge had advanced to that of Thomas Andrews – the analogy is indeed close because the risk of incorrect administration of thiopurine drugs in at least some patients is a risk to life.

    In reply to Muenchen’s post, the potentially novel feature of the final version of the claim is the hitherto undiscovered link between an immune-mediated gastrointestinal disorder, a therapeutically effective dose of a drug providing 6-thioguanine, risk of leucopenia and a level of 6-thioguanine within the range 230 – 400 pmol per 8×10^8 red blood cells. That kind of link has commonly been recognized in the EPO as amounting to a technical feature (e.g. by the Enlarged Appeal Board in Mobil Oil III/Friction reducing additive), and is also recognized by the USPTO, I believe, in medical treatment claims. It would be a serious consequence if this kind of link was held to be insufficient to support patentability, but it is difficult to see on the principles set out by Justice Breyer where the ambit of s. 101 ends. Leaving it to arbitrary decisions (the length of the Lord Chancellor’s foot) is not helpful.

    However, there is still the inventive step case against.

  13. MaxDrei May 8, 2012 5:52 am

    Thanks for the answer Paul and the nod to EPO-style “use” claims. But for the publications prior to the filing date, might there not even have been room here for an EPO-style use claim founded on the discovered link, which would have been novel and inventive even without recitation of the 230 and 400 upper and lower limits?

    I’m not disputing the novelty, just musing on the practicalities of how to claim it successfully. Was it not in your excellent book that I read something about claiming the novelty but describing the inventive step?

    But anyway, I did enjoy the reference to the length of Lord Chancellor Breyer’s foot. That would of course influence the size and weight of his boot, and how far he could kick with it.

    Reverting to your analogy, it is useful on the relationship between information and invention. I infer that Andrews was the actual devisor of any “link” invention embodied in the Titanic. But I am having difficulty imagining his ever perceiving that link to be an “invention”, or his ever making the link the subject of a patent application. That helps to make his link “invention” non-obvious, I suppose.

  14. step back May 8, 2012 6:54 am

    Paul,

    Thank you for your article –basically calling a rat a rat rather than a slightly less than cute fur toy.

    IMHO, the “Titanic analogy” is misguiding and unhelpful.

    Whether there was a useful contribution to society (i.e. the passengers of the sinking Titanic) is besides the point.

    What is the point is that 35 USC 101 says a “process” is a patent eligible type of invention.

    1) It goes beyond the pale to say that inputting metabolizable drugs into a human body is not part of a “process”, a chemically transformative process.

    2) It goes beyond insanity to say that extracting blood from a live human body and chemically testing the blood to detect the concentration of a specific compound (a specific metabolite) so as to determine the health status of the patient is not a “process”.

    Yet 1) and 2) is exactly what SCOTUS did in MvP, plain and simple.

    One need not divert one’s mind off to some long past historic event in the North East Atlantic to figure out what is going on. One need not analogize to the Carpenter and the Walrus. To say that a clearly chemical process is not a “process” is sheer Jabberwocky. How did we get to the point where we can’t see that the Emperor parades in clothes made of nothing but fictional Jabberwocky?

    http://www.jabberwocky.com/carroll/jabber/jabberwocky.html

  15. Paul Cole May 8, 2012 7:19 am

    @step back: I agree with your sentiments about the process, the blood sample and the chemical test (if not perhaps with the force with which they are expressed). Indeed your sentiments follow the CAFC which IMHO got it right. The Titanic example is simply to help those with non-chemical backgrounds gain a clearer understanding of the issues involved.

    Methods of testing have long been patentable. What you are testing for and how the test is to be interpreted are arguably technical features of the test. The EPO appears to be of that view. If a contrary view is adopted in the US, then a patentable test becomes ineligible subject matter simply because the way in which the test is claimed includes interpretation features. There is a string of earlier patents, not confined to the chemical arts, that would be nullified on this hypothesis.

    And we can have oscillating patentability features. Without the interpretation it is patent-eligible but not novel. With the interpretation it becomes novel but patent ineligible. It is submitted that senior courts should not make findings that on interpretation lend themselves to ridicule.

  16. patent litigation May 19, 2012 4:31 pm

    Numerous commentators have noted that the Court has relied too heavily on §101 in deciding recent patent cases. Perhaps avoiding the patent-eligibility issue would also help the Court to avoid so much controversy over the outcomes of its patent decisions.
    http://www.aminn.org/patent-legislation

  17. Stan E. Delo May 20, 2012 2:19 am

    patent litigation-

    Perhaps the court should have considered all three areas of what constitutes an *invention* here in the US. As in 101, 102, and especially 103 objections. Unfortunately the Supreme Court decided to just punt I guess, by tossing the invention into the trash bin with a 101 decision, and left it at that.

    Point of order- What about 102 considerations?

    SD~