KSR Extended to Obviate Component Purified from Known Mixture

Aventis Pharma & King Pharma v. Lupin Ltd. (Fed. Cir. 2007).

Altace is the King/Aventis brand of ramipril – a top-selling ACE inhibitor.  The patent claims ramipril formulated “substantially free of other isomers.” The district court found the patent not invalid, but only by a slim margin. On appeal the CAFC reversed – finding the patent invalid as obvious.

Prior Art: One reference (‘944 patent) was filed as a continuation-in-part of an already abandoned patent application. That application was eventually revived, but Aventis argued on appeal that the ‘944 patent should not be awarded the filing date of the parent.  The CAFC found this a potentially interesting argument, but refused to hear the argument because Aventis had failed to make the argument at the district court level.

The appellate panel also agreed that the experimental results of a Shering Doctor constituted 102(g)/103(a) prior art because the Doctor had not abandoned, suppressed, or concealed her prior invention.

Obviousness of a Purified Form: The district court, ruling pre-KSR, found the patent nonobvious. On appeal, the CAFC took a different view – finding that the purified form of a known mixture is prima facie obvious if a PHOSITA would have some reason to believe that the mixture derives properties from particular components.

However, if it is known that some desirable property of a mixture derives in whole or in part from a particular one of its components, or if the prior art would provide a person of ordinary skill in the art with reason to believe that this is so, the purified compound is prima facie obvious over the mixture even without an explicit teaching that the ingredient should be concentrated or purified.

The prima facie case of obviousness is especially difficult to rebut where, as here, the potency of the mixture varies directly with the amount of isomer in the mixture.

The court implicitly distinguished this case from Forest Labs — noting that obviousness may be rebutted by showing difficulty in purifying the mixture.

[A] purified compound is not always prima facie obvious over the mixture; for example, it may not be known that the purified compound is present in or an active ingredient of the mixture, or the state of the art may be such that discovering how to perform the purification is an invention of patentable

Reversed, Patent Invalid as Obvious

18 thoughts on “KSR Extended to Obviate Component Purified from Known Mixture

  1. NECROMANCER! Causing a long dead thread to arise shall be punishable by excommunication!

    Don’t see many of your kind around these parts.

  2. First, I think we should distinguish between two different questions:

    1. Is it obvious to purify a compound?
    2. Is it obvious to resolve one stereoisomer from a mixture of stereoisomers?

    1. Purifying a compound includes, for example, purifying a protein, isolating a final product from a crude reaction mixture, and other separation techniques. Purifying a known compound is a large part of synthetic laboratory chemistry. It is obvious. Sometimes the difficulty lies in “discovering how to perform the purification.” Aventis v. Lupin. If the purification is accomplished in an inventive way it would give substance to a METHOD of purifying claim. But purifying a compound from a mixture does not make the COMPOUND inventive.

    2. A single compound (including a purified compound) can include two or more steroisomers, for example, the R and S enantiomers of a racemic mixture. Often one stereoisomer is responsible for most or all of a compound’s activity. Resolving a mixture of stereoisomers to isolate each individual stereoisomer is obvious. Resolving a stereoisomer may be achieved via a creative or innovative route, deserving of a METHOD patent drawn to the route. But resolving a stereoisomer from a mixture of stereoisomers does not make the COMPOUND inventive.

    Note (above) I use the word “inventive” to express my opinion. I believe the case law indicates that purifying or resolving compounds may make the compounds themselves patentable.

  3. Back in 2000, The EPO Technical Board of Appeals had the following comment regarding Lipitor:

    “The Examining Division held that the person skilled in the art would have expected that one of both enantiomers, resulting from splitting the racemic mixtures of [US Patent No. 4,681,893], exhibited a higher hypocholesterolemic activity than the racemic mixture.
    The extent of that expected increase in activity was not to be regarded as an indication of inventive step.”

    D E C I S I O N of the Technical Board of Appeal 3.3.1 of 20 July 2000 (link to legal.european-patent-office.org)

    Is the U.S. getting ready to follow the “common sense” approach the Examining Division seems to take to claims to sepcific enantiomers of known racemic mixtures?

  4. An anonymous comment picked up on the thalidomide—it is true that nature likes optical isomers—all the amino acids for example. However the general rule is non-activity or lower activity of the other isomer—-atropine, thyroxine etc. The point I was trying to make is that where a mixture is active and gets approval it should be clear that both isomers either contribute to the activity or at least do not interfere with that activity-thus the purification of one isomer does not award a surprise-how about cetirizine as a recent example or omeprazole versus esomeprazole.

    These are what would appear to be obvious. The point of the thalidomide example [in retrospect] is that whereas the racemate should not have been a drug [and indead might have been preempted by a publication] the isolation of the active-non toxic isomer-should indeed be rewarded.

    Hope that is a little clearer,

    Malcolm Rss

  5. It’s not clear that this ruling will wipe out all chiral drug patents, and I don’t think it should. In the case at hand, it was well-known in the prior art that the S-isomer of ACE inhibitors was the active species. The inventors isolated the S-isomer of ramipril and, unsurprisingly, it was the active species. New and useful, yes, but about as obvious as you can get in medicinal chemistry. Nothing surprising in the results.

    Absent a teaching in the prior art, as we had in this case, I don’t think it’s at all obvious what will happen when you isolate a single isomer or enantiomer. It’s obvious to try, to see if you can improve the properties, but I think the “reasonable likelihood of success” is not there. Will one of the isomers be usefully different from the racemate? If so, will toxicity be found in the active or inactive isomer? What about side effects? Does the physiological effect of the racemate rely on a combination of two effects from the two isomers?

    You can look to the experience of Sepracor, a company founded largely on the idea of resolving the enantiomers of successful racemic drugs: some success may be had, but it’s very far from being guaranteed.

  6. Malcolm Ross wrote : “Thus thalidomide, which was originally a mixture where one isomer, unfortunately, proved teratogenic, would still, under the new rulings, have received patent protection because it was and would be unexpected that one isomer would be toxic and the other not.”

    Absolute nonsense.

    In fact, in nature it is the exception, not the rule, that the two stereoisomers in a racemic mixture will have the same biological effect.

    Much more often there is a single stereoisomer that has an effect and the other(s) does not.

    From my seat, and I’m not even a PHOSITA, it would see excruciatingly obvious that one stereoisomer in a racemic mixture is bioactive and the other does not have that same bioactive effect.

    This is why, for example, the vitamins you get in bottles are often a huge percentage of non-active stereo isomers (such as vitamin E).

    Why? Because at every step in the synthesis of the vitamin where a moiety can be added in multiple stereospecific sites, you get a mixture of stereo isomers out.

  7. Surely we have started to get rid of some of the evergreening practices-maybe then companies will concentrate their efforts on innovation rather than prolonging patent life beyond all previously known limits.

    With regards isomers it seems to me that the only way to get patent protection is if it can be demonstrated that by getting a pure isomer there is an unexpected advantage-the traditionally correct-it was surprising-approach. Thus thalidomide which was originally a mixture where one isomer unfortunately proved teratogenic-would still under the new rulings have recieved patent protection because it was and would be unexpected that one isomer would be toxic and the other not.

    The amount of work done in order to ascertain this would not have been trivial and should be rewarded.

    So all we seem to be seeing is an application of well known principles rather than what has been at best some tenuous arguements about what is obvious.

  8. “Funny thing: if the disputed CIP prior art reference had been prosecuted under the new rules, then the prosecution history would have contained statements from the patentee about what was and was not contained in the progenitor cases.”

    In the future, maybe a computer device programmed with special “software” can be used to determine the differences between the text in two related documents. While impractical today, such technology may become commonplace in the 22nd century.

  9. “However, if it is known that some desirable property of a mixture derives in whole or in part from a particular one of its components, or if the prior art would provide a person of ordinary skill in the art to believe that this is so, the purified compound is prima facie obvious over the mixture even without an explicit teaching that the ingredient should be concentrated or purified.”

    Does this leave any room for a single stereoisomer to ever be patentable? I suppose it does, but not much: if the other stereoisomer(s) in the mixture are also shown to be active, then maybe you can argue it’s not prima facie obvious to isolate one or the other.

    Funny thing: if the disputed CIP prior art reference had been prosecuted under the new rules, then the prosecution history would have contained statements from the patentee about what was and was not contained in the progenitor cases. Which might have spurred Aventis’ trial attorneys into challenging the dates on which the CIP was presumed to be prior art, something they apparently didn’t think to do in the actual case.

    Nice try on the part of the panel to distinguish over last week’s Forest Labs case, but to me it doesn’t wholly wash: if in the early 1990′s doing a separation of two enantiomers on a chiral column wasn’t obvious (Forest), how can you say that in the early 1980′s providing a pure composition containing one of numerous possible stereoismers (32? 5 stereocenters = 2^5) was prima facie obvious?

    But Inquiring Mind’s probably right – who needs drug patents? All diseases have been cured anyway, right?

  10. Inquiring Mind – Eliminating patents for isolating naturally occurring protein and DNA sequences should not affect Big Pharma’s ability to patent new drugs. (Unless they were simply bioprospecting and ripping off native cultures in the first place.)

  11. it’s really quite simple.

    Isolating DNA may be tricky/worthwhile/time consumming/etcetera, but it is not inventive.

    I don’t disagree that we should offer an incentive to folks for DNA sequencing.

    I just don’t think smashing into a patent system based on “novelty” was the way to do it.

  12. could it be that genes are difficult to “purify”, or at least were?

    and it’s strange that “difficult to purify” is differentiating, but maybe that allows “true” novelty to get patents while condemning derivative work that too closely mirrors the previous innovation.

    they seem afraid of being made obsolete. this case will be brought up as fodder in the senate hearings.

  13. Good point, Gideon; too bad for all the patentees out there that isolated protein and DNA and their sequences have been patentable for such a long time. Think of all the money we’ve all wasted pursuing patents on these things. And bye, bye, Pharma–at least now we won’t have to worry about the new rule changes, because there won’t be enough patent protection available to make Pharma worthwhile as a business pursuit. Gee, where are we going to get new drugs? Good thing all the diseases have been cured already.

  14. APalmer- I don’t get the joke either way.

    2 thoughts on this case:

    1. genes and naturally occurring protein and DNA sequences should never have been patentable in the first place. There is no invention to isolating and sequencing the endogenase X enzyme.

    2. It’s remarkable that any cogent human being thinks that an “isolated” protein could be novel and nonobvious when the sequence of the protein is already known.

  15. Errr…

    That should have been ‘Your lupins or your life’ – a very weak piece of humour and I muffed it.

  16. Let me first admit that I only skimmed this decision, so forgive me if I say something incorrect or off-base. But, this case really doesn’t seem all that surprising, and I wonder if the outcome really would have been different pre-KSR.

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