Federal Circuit Review of Patent Term Extensions

By Jason Rantanen

During the summer, the Federal Circuit is a relatively quiet place.  The judges often take their non-sitting months during this time, and the pace of opinions tends to drop.  Thus, for the next few weeks, I'll mostly be posting summaries of cases that issued this past spring and early summer.  The two cases discussed below deal with a relatively minor — but still important issue in the pharmaceutical and medical device context: patent term extensions based on extensive regulatory review periods. 

Ortho-McNeil Pharmaceutical, Inc. v. Lupin Pharmaceuticals, Inc. (Fed. Cir.  May 10, 2010)
Photocure ASA v. Kappos
(Fed. Cir. May 10, 2010)

35 U.S.C. §156 allows a patentee to obtains a term extension if the patent covers a product that has been subject to a regulatory review period before it can be marketed or used.  Pharmaceuticals and medical devices are subject to such a review period, and new drug products in particular often involve a lengthy application and testing process.  The initial determination as to whether a patent term extension should be granted is made by the USPTO, in consultation with the FDA.  That decision is subject to review or challenge in district court proceedings.

One of the key issues in determining whether a patent term extension is warranted for a drug is whether it is the first time regulatory approval has been granted for this particular drug product, a determination that turns on whether or not the "active ingredient" had previously been approved by the FDA.  Ortho-McNeil and Photocure, both authored by Judge Newman and issued on the same day, provide an interesting contrast on this issue. 

Ortho-McNeil v. Lupin
In Ortho-McNeil, the extension issue arose in the context of an injunction entered against Lupin Pharmaceuticals prohibiting it from making, using, selling, etc. a drug product covered by U.S. Patent No. 5,053,407 (the '407 patent) during the extension period.  In that case, the district court affirmed the PTO's determination that an enantiomer was a different drug product then its racemate. In doing so, the district court noted that the PTO's determination should be afforded great deference.

Note: Enantiomers are molecules that are mirror images of one another.  Due to their different orientation, they have different properties.  A racemate is a composition consisting of equal parts of the two enantiomers.  The '407 patent covered a substantially purified form of one of the two enantiomers (levofloxacin) in the racemate ofloxacin.  There was no dispute that levofloxacin was separately patentable from ofloxacin.

On appeal, the Federal Circuit agreed with the district court, concluding that there was no basis for challenging the established FDA and PTO practices of treating enantiomers as different drug products and rejecting Lupin's legislative intent argument.

Photocure v. Kapos
Photocure involved a contrary determination by the PTO: that the drug product at issue was not a different "active ingredient," and thus the patentee was not entitled to an extension.  In Photocure, the product at issue ("MAL") was a methyl ester of a compound ("ALA") that had previously been approved for the same therapeutic use.  While the FDA treated MAL as a new drug, requiring a full approval process, the PTO rejected the extension based on its conclusion that § 156(f)(2) does not mean the product approved by the FDA, but rather the "active moiety," which it concluded was the same in both MAL and ALA.

Both the district court and Federal Circuit disagreed.  In rejecting the PTO's interpretation of 156(f)(2), the Federal Circuit reasoned that § 156 focuses on the product that is subject to approval by the FDA, not the underlying pharmacological mechanism. Furthermore, Skidmore and Chevron deference standards did not apply because the statute was not unambiguous and the PTO's interpretation was neither persuasive nor consistent. 

Note: although not the primary focus of the opinon, the panel also concluded that the PTO was wrong even under its  "active moiety" interpretation as the biological properties of ALA and MAL are indisputably different.

* * * *

In addition to the issues discussed above, the scope of the injunction in Ortho-McNeil is worth noting.  Although the extension authorized by 35 U.S.C. § 156 covers the "selling" or "using" of the product covered by the patent, the district court enjoined Lupin from engaging in any of the traditional forms of direct infringement, including "making" or "importing."  Despite the literal language of §156, the Federal Circuit affirmed the scope of this injunction because there are no non-pharmaceutical "uses" of the drug product, a point that Lupin apparently conceded.  Although as a practical matter this distinction may be of little value, as pharmaceutical companies often have production facilities located outside the United States, it is something to consider when seeking or opposing litigation under § 156. 

40 thoughts on “Federal Circuit Review of Patent Term Extensions

  1. I would hazard a guess that when one racemate is at all beneficial and the other is toxic, that the INANE point just made would be easily met.

    Deadly Logic isn’t so deadly when it doesn’t know what words mean.

    Ok, now I can officially admit that this discussion is way over my head.

    The two enantiomers are identical except for how four different groups are arranged around one of the carbons. When drugs are created in a big vat in a lab, there’s usually no control over which of the arrangements you get, so they form randomly and you get an equal (racemic) mixture of both.

    Sometimes the body does that too. Even if you give it only one of the two enantiomers, the body processes that one in a way that randomly rearranges the molecule around the stereocenter, so that you get back the racemic mixture. Like if you separated a bunch of pairs of mittens and gave someone all the right mittens, and they randomly turned every second one inside-out so they became left mittens again. Kind of a waste of time to separate them if you know that’s going to happen.

  2. The introductory note is sort of lame. The Federal Circuit isn’t that much slower during the summer months. And it certainly isn’t a relatively quiet place.

    Even if a few judges take off in August, there’s an internal process reason why many opinions issue in late summer.

  3. The enantiomer can be converted to the teratogenic enantiomer in vivo, so you cannot say that the drug is not teratogenic in any practical sense.

    Ok, now I can officially admit that this discussion is way over my head. I suppose that need not stop me from opining, though…

  4. if you find out that one enantiomer is like ten times more therapeutically effective than the racemate or something

    I would hazard a guess that when one racemate is at all beneficial and the other is toxic, that the INANE point just made would be easily met.

  5. No such thing as synergistic effects in someone’s world

    Synergistic effects of separating two known chemicals?

    Sure, if you find out that one enantiomer is like ten times more therapeutically effective than the racemate or something, you can have your patent.

  6. You have a mixture of two things that has a number of properties.

    No such thing as synergistic effects in someone’s world

  7. Unexpected results, my friend.

    You have a mixture of two things that has a number of properties. You separate the two things, and each of the two things has some of those properties. You then point to the one that has more of the properties you liked so much about the mixture.

    What is unexpected about that result?

  8. Yes, but the racemate has both effects, and you’d know beforehand that if you separated the enantiomers you’d get one with the first effect and one (perhaps the same one, perhaps not) with the second effect.

    Cause and effect is not nearly so black and white in biochemistry.

    If the stereocenter is important to the function of the drug, you pretty much always have some desire to separate the enantiomers.

    Unexpected results, my friend. In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978). They have to be significant in comparison to the expected results, but the law hasn’t completely committed itself to obvious-to-try.

    You’re free to argue for the law as you’d like it to be, but that is not the law as it is.

  9. Then patentability is not the predominant factor in the desire to develop the drug, right?

    Patentability is not the predominant factor in deciding which of the two to sell, once both are available.

    Patentability is the predominant factor in the desire to develop the drug, because nobody would incur the expense if they couldn’t earn the money back.

    Pharmaceutical methamphetamine is sold in dextro and levo forms because they have different effects on different aspects of the nervous system.

    Yes, but the racemate has both effects, and you’d know beforehand that if you separated the enantiomers you’d get one with the first effect and one (perhaps the same one, perhaps not) with the second effect.

    *The enantiomer can be converted to the teratogenic enantiomer in vivo, so you cannot say that the drug is not teratogenic in any practical sense.

    It’s probably safe to say that this discussion does not apply to self-racemizing compounds, because they are effectively impossible to separate.

    If the stereocenter is important to the function of the drug, you pretty much always have some desire to separate the enantiomers. Chances are, one of them will be the drug you really want, and the other will be effectively like giving the same patient a random completely unrelated drug that will have some undesired result wherever its stereocenter finds a receptor.

    Besides which, it’s probably enough to make a case for non-obviousness that so many drug companies spend so much money separating so many known racemates, only to show up in court later and claim that they never would have thought to try doing what they did.

  10. Because their customers prefer drugs with fewer side effects.

    Then patentability is not the predominant factor in the desire to develop the drug, right?

    Both known enantiomers have known properties, it’s just a question of whether each property belongs to the one or the other.

    Natch. If you haven’t isolated the enantiomers, then you cannot say that the enantiomers have known properties. You know that a therapeutic property is present. You do not know which enantiomer or enantiomers have the observed property, whether different enantiomers have differing physiological properties and/or effects, etc. Thalidomide has an enantiomer that is less teratogenic*. Pharmaceutical methamphetamine is sold in dextro and levo forms because they have different effects on different aspects of the nervous system.

    The pharmaceutical properties of the enantiomers are not necessarily known simply by virtue of knowledge of the properties of the racemate. Separating the racemate may be obvious, but the result may not. Secondary considerations, my friend.

    *The enantiomer can be converted to the teratogenic enantiomer in vivo, so you cannot say that the drug is not teratogenic in any practical sense.

  11. Perhaps becuase each particular racemate is itself novel and non-obvious?

    No, the racemate is already known, and usually patented, by the time someone manages to separate it.

  12. So why is anything other than the clever method of separating that particular racemate entitled to a patent?

    Perhaps becuase each particular racemate is itself novel and non-obvious?

  13. Okay, so, there are all kinds of therapeutic and economic reasons to separate enantiomers, and all kinds of reasons to expect one enantiomer to be better than the other. Both known enantiomers have known properties, it’s just a question of whether each property belongs to the one or the other. In particular, it’s obvious that at least one of the two will be at least as therapeutically effective as the racemate.

    It appears the patentability resides solely in how hard and expensive it is to separate them. So why is anything other than the clever method of separating that particular racemate entitled to a patent?

  14. also, if you have protection over one configuration, it would most likely hold water over the racemic mixture if that particular configuration is the “active” ingredient.

  15. Which begs the question, why would any competitor or third party want to produce the enantiomer rather than the racemate?

    Because their customers prefer drugs with fewer side effects.

  16. But by far the most desirable property that justifies the expense is the fresh patent you can get on whichever enantiomer turns out to be the good one.

    Which begs the question, why would any competitor or third party want to produce the enantiomer rather than the racemate?

    Certainly not a justification for the patentability of the isolated enantiomer, but you’re suggesting that the benefit of a patent on the enantiomer is the predominant consideration. Such a patent is nigh worthless if the racemate is functionally competitive and cheaper to produce.

  17. “In extreme cases, one enantiomer may have almost the entire therapeutic effect while the other has almost all the side effects.”

    Not so. More times than not, one configuration is therapeutic, while the other configuration is extremely toxic. That is not an extreme situation. A little chemistry; when synthesizing a compound with a chiral center, the synthesis will usually go forward to yeild both the R and S configurations. Industrially, this mixture is just fine because only one configuration will be utilized and the other is simply waste. In the body, only one configuration is typically active whereas the other will be either (1) inert or (2) toxic.

    If one configuration is therapeutic and the other is toxic, the therapeutic configuration will need to be isolated. Now the tricky part: isolation. Yes, there are some standard methods to seperate enantiomers, but the methods are tailored to each specfic molecule. This can very well take years to develope. Think of it this way; you are trying to seperate two IDENTICAL molecules but for there spatial orientation. More or less, any reaction that affect one configuration will do the same to the other.

    Re market pressure etc…say you have a racemic mixture. where, one configuration is the therapeutic ingredient and the other is not. i dont see how it would be obvious to try the other configuration. the prior art would indicate that the other configuration is inert, or better yet toxic = teaching away from the trying. (bayer v. barr type situation).

    cheers.

  18. Sure – bu tseparating for the one you want does not create or resolve any particular need or market pressure for the other.

    When you’re separating wheat from chaff, you only need a reason to want the wheat. Or the chaff. Or know that you’ll want one of them, which you can readily identify after separating the two.

    If your bread comes out full of chaff, that’s motivation enough to find a way to separate the part that makes delicious bread (whichever one that turns out to be) from the part that makes disgusting bread.

  19. Re: IANAE’s response to “design need or market pressure to solve a problem “:

    Sure – bu tseparating for the one you want does not create or resolve any particular need or market pressure for the other.

    This thought was anologized above with the wheat and chaff.

  20. My understanding is that isolated enantiomers often have properties (e.g., less side effects) that are more desirable than the mixtures.

    In extreme cases, one enantiomer may have almost the entire therapeutic effect while the other has almost all the side effects.

    But by far the most desirable property that justifies the expense is the fresh patent you can get on whichever enantiomer turns out to be the good one.

  21. Don’t you need at least some reason why someone would be interested in separating that particular enantiometer in the first place?

    My understanding is that isolated enantiomers often have properties (e.g., less side effects) that are more desirable than the mixtures. That’s why people isolate them, in spite of the expense of doing so.

  22. Don’t you need at least some reason why someone would be interested in separating that particular enantiometer in the first place?

    People are clearly interested in separating them in the first place. They’re doing it, and look how expensive it is!

  23. smashmouth, you didn’t highlight the “When there is a design need or market pressure to solve a problem” part of the sentence. Don’t you need at least some reason why someone would be interested in separating that particular enantiometer in the first place? I’m out of my field here, so forgive me if this is an ignorant question.

  24. In KSR v. Teleflex, 550 U.S. 398 (2007), Justice Kennedy wrote for a unanimous Court:

    “When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.”

    Id. at 421 (emphasis added). Seems to me separating an enantiomer from a known racemate pretty much fits the bill, unless something specific about the method used is inventive.

  25. but, you are assuming you can, or easily, seperate the mixture.

    I don’t know how enantiomers are usually separated. It’s my understanding that there are a handful of standard methods that sometimes work but don’t always. Surely those are obvious to try.

    When those standard methods fail, I’d like for someone to explain what happens next. Is it merely expensive and time-consuming to try other methods, or do you actually have to get creative to tailor your separation method to the particular molecule, e.g. a chiral enzyme that binds to the stereocenter or replicating the in vivo receptor where the drug acts?

  26. @ianae
    all good. but, you are assuming you can, or easily, seperate the mixture. i don’t see a KSR problem at all if the prior art only discloses one enantiomer. as you said, usually only one of the enantiomers is of interest for human use. for every citation to prior art teaching towards trying the other enantiomer, you can find just as many teaching away. all i’m getting at, i’m not sure if stereochemistry experiments are obvious to try.

  27. it’s a crap shoot to predict the properties of one enantiomer over another.

    Sure, you can’t predict how the specific properties will divide up between the two enantiomers, but you have some reason to expect the two enantiomers might have different properties, since most naturally-occurring biochemistry is chiral and all this fuss has been made over other single-enantiomer preparations in the prior art.

    Once you separate them, it’s trivial to test them both and see which one works better. There are only two of them. You don’t have to know in advance whether you’d prefer the levo or the dextro, you only have to know in advance that you’d like to see which of them is better at doing what the racemate does.

  28. re obvious to try. it’s a crap shoot to predict the properties of one enantiomer over another. as previous posts mention, enantiomers are usually synthesized to yield a racemic mixture; where one enantiomer is the bioactive candidate and the other is usually benign. i dont see the obvious to try argument holding any ground when strictly speaking about a racemic mixture — add some prior art to the argument, then you may have something.

  29. When separation is not routine it can be hard as hell and take years.

    Does it take years because you have to try more different well-known methods that happen to be more expensive or less reliable or less convenient to implement, or because you need to develop a unique way to separate them that only works on that one particular substance?

  30. “I see no commentors thus far spent life working as an organic chemist. When separation is not routine it can be hard as hell and take years. But go ahead armchair scientists.”

    My beef is that the composition of matter shouldn’t be patentable under your scenario. Your non-routine process, however, may well be.

  31. I see no commentors thus far spent life working as an organic chemist. When separation is not routine it can be hard as hell and take years. But go ahead armchair scientists.

  32. Funny thing – the EPO will generally regard an enantiomer as lacking inventive step over the previously disclosed racemate, because separation of enantiomers is considered to be routine. Max, are there situations in which the EPO will nevertheless grant a patent on an enantiomer?

  33. “That’s why when you are developing something obvious you should always be sure to waste time and do it wrong a couple times first, just to make sure you have some secondary factors to throw around.”

    Mooney, I don’t at all share your political views and sometimes you annoy the hell out of me, but that comment is one of the funniest I’ve read in many months, and you deserve major credit. Brilliant explanation of the Graham factors. What’s crazy is that your satire isn’t that far from the truth. We live in insane times.

  34. It was Saint Newman who famously held an enantiomer non-obvious over a racemic mixture because it cost a lot of money to isolate (although it was ultimately isolated by an old, well-known technique).

    Is it time to reconsider the Mexican yellow bean patent yet? A racemate is kind of like a bag of mixed beans, right? Except for the shocking result that some of the “beans” have some of the properties of the racemate, and the rest of the “beans” have the rest of the properties of the racemate.

  35. Talk about “obvious to try.” KSR hasn’t made it here yet, apparently.

    It was Saint Newman who famously held an enantiomer non-obvious over a racemic mixture because it cost a lot of money to isolate (although it was ultimately isolated by an old, well-known technique).

    That’s why when you are developing something obvious you should always be sure to waste time and do it wrong a couple times first, just to make sure you have some secondary factors to throw around.

  36. Not my area, but wouldn’t the analogy of separating wheat from chaff apply? The known good stuff (wheat) is one thing, and then, instead of simply throwing the chaff into the fire, investigating and finding something of value in the chaff creates the “invention”? Even if the “surprising” aspect is minimal, the fact that something distinhuishing is found provides the acceptible path to the separate patent.

  37. “There was no dispute that levofloxacin was separately patentable from ofloxacin.”

    Here’s a big part of the problem. Section 103 ought to preclude patenting the enantiomer in nearly all cases. Obviousness is applied too weakly in this context, especially when the only hard part is often the method of isolating the enantionmer from the racemate, not the allegedly “surprising” new properties of the enantiomer, which all too often are overblown and not so surprising at all. Talk about “obvious to try.” KSR hasn’t made it here yet, apparently.

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