Routine Experimentation -> Obvious

Pfizer v. Apotex (Fed. Cir. 2007).

Norvasc® is Pfizer’s patented blockbuster drugs for treating hypertension and angina.  The Court of Appeals for the Federal Circuit (CAFC) has invalidated Pfizer’s patent — finding it obvious. Generics are already on the market.  

Background: Apotex, a generic manufacturer, filed a notice with the FDA — certifying its belief that Pfizer’s patent covering Norvasc was invalid and unenforceable. The trial court upheld Pfizer’s patent and issued an injunction stopping Apotex from making a generic version.

Courts and the PTO: In its appellate opinion, the CAFC began with a strong repudiation of any reliance on Examiner’s findings during prosecution of a patent: “Our case law consistently provides that a court is never bound by an examiner’s finding in an ex parte patent application proceeding.”  Applying this boundary, the panel found that “it can never be the case that an examiner’s interim finding of prima facie obviousness renders the claims of an issued patent prima facie obvious.” 

Unpredictably Obvious: Norvasc is amlodipine besylate.  At the time of the invention, amlodipine was known as was the use of besylate anions.  Pfizer argued that the results of combining these would have been unpredictable and therefore non-obvious.  The CAFC disagreed, finding that unpredictability does not result in nonobviousness.

[A] rule of law equating unpredictability to patentability, applied in this case, would mean that any new salt … would be separately patentable, simply because the formation and properties of each salt must be verified through testing. This cannot be the proper standard since the expectation of success need only be reasonable, not absolute.

Here, the court found plenty of evidence to believe that a PHOSITA would have had a reasonable expectation of success.

Obvious to try: A combination can be “obvious to try” but still be nonobvious.  This is may be true, for instance, in cases where there are many potential parameters or where the art merely suggests a “general approach that seemed to be a promising field of experimentation.” The court distinguished those situations from the present case — finding that a PHOSITA would have been able to narrow the group of potential salt-formers to fewer than 53 anions, which would be an acceptable number to form “a reasonable expectation of success.”

Routine Experimentation: Start telling your story!!  It is axiomatically true that patentability is not negated by the manner in which the invention was made.  The exception, found here, is that “routine testing” can be considered a reason to invalidate the patent.

[T]he prior art provided not only the means of creating acid addition salts but also predicted the results, which Pfizer merely had to verify through routine testing.

Secondary Factors: On appeal, the CAFC also held that it was an error to consider Pfizer’s switch from a different form of amlodipine to amlodipine besylate as a secondary factor of obviousness.  Furthermore, comparison of unexpected results must compare the invention to the closest prior art — not to the closest commercial product.

Orange Book Issues: Mylan was first to challenge the patent and lost.  Under the Orange Book rules, Mylan still qualifies for six-months as the exclusive generic seller.  Apotex, which won this case, claims that it also has rights to begin selling a generic version as soon as the FDA gives its approval. Apotex, however, has not presented its legal claim.

Expiration: When $2.4 billion per year are at stake, every day counts.  The patent was set to expire on Sunday, although Pfizer claimed six additional months of exclusivity based on its testing of childhood eficacy.

Notes:

  • The patent had previously been upheld by three separate district courts.

28 thoughts on “Routine Experimentation -> Obvious

  1. Dino,

    Forget about ANDA — the Orange Book says that Dr. Reddy’s had an amlodipine maleate product approved in 2003, but has since been discontinued.

    If Dr. Reddy’s could have been on the market with the maleate version after the expiration of the first amlodipine patent, then they could have gotten a share of the amlodipine market ($2.5B/year) from Pfizer between the expiration of the first patent and the expiration of the second. Why didn’t they do this??

    The implication is that there is a significant improvement with the besylate salt, and normally that is given weight under “secondary considerations” — but the CAFC would have none of it in this case. IMHO, their jurisprudence has really lost a lot of credibility over the last ten years or so, especially decisions by certain judges.

  2. Sean said:

    Why wouldn’t Mylan, Apotex, etc. have been on the market some time ago with an amlodipine maleate? If there is really nothing about amlodipine besylate that is so much better than amlodipine maleate, then why isn’t amlodipine maleate marketed?

    Sean, the easy answer is that generics can’t file an ANDA on amlodipine maleate since Pfizer never filed an NDA on it. Generics are in their business precisely because they piggy-back off of the clinical data the innovator company has submitted to the FDA. All they have to show is that their drug is bioequivalent to the NDA drug.

    I’m pretty sure that the salt also has to be the same as the NDA and that you can’t just trade off a different anion. Even if that is not a legal requirement, I think it is difficult to get bioequivalency if you don’t have the same salt.

    Anybody care to confirm this last statement?

  3. Doh. Call me stupid, but I don’t see anything in the literal originalist language of Article I, sec. 8, clause 8 that says “… but only if the respective Discovery is not obvious to one of ordinary skill.”

    Not much of a discovery if it’s obvious, is it?

    To render the word discovery to mean notice vaporizes the meaning of the word.

  4. “Progress is promoted when you create a contest ..”

    Progress is impeded when the government enforces monopolies. Whether the patent system promotes or impedes progress depends on the relative size of those two effects. One cannot simply assume that patents on balance promote progress since it makes your argument circular.

    If on balance the patent system, or some severable aspect of it, impedes progress then the system or the aspect are unconstitutional.

  5. “To promote the Progress of Science and useful Arts, by securing for limited Times to Authors and Inventors the exclusive Right to their respective Writings and Discoveries.”

    Doh. Call me stupid, but I don’t see anything in the literal originalist language of Article I, sec. 8, clause 8 that says “… but only if the respective Discovery is not obvious to one of ordinary skill.”

    Also I don’t see where it says to “Initiate the Progress of the Useful Arts”. It says “Promote”, meaning to raise such progress to the next higher level, and not meaning to cause progress to happen in the first place.

    Progress is promoted when you create a contest, when you reward the first who gets to the finish line ahead of others even if the others “couldah and shouldah” and all that other good stuff spouted by the enemies of the American patent system.

    It would be nice if people who wave the flag in one hand and the Constitution in the other actually read the darn thing from time to time. Of course, reading and thinking are hard hard things to do. Fuzzy foaming from the mouth is so much easier to do. So let’s stay the course by continuing to engage in wild hand waving and unbounded thinking of the fuzzy kind.

  6. To take the language of the statute literally – that inventions only need to be not obvious to a person of ordinary skill – is to set the bar unconstitutionally low. If we define ordinary skill to be those persons lying within one standard deviation of the mean then 15% of the those skilled in the art will have above ordinary skill. An invention could be immediately, even laughably, obvious to that 15% and yet be patentable on a literal reading of “obvious”.

    To go even further than a literal reading and to say that something is only “obvious” if there is some TS or M (sounds vaguely dirty, doesn’t it?) is to move even farther from the constitutional authorization for the grant of patents.

  7. For those who think NORVASC is a “me-too” drug, please respond to this:

    Why wouldn’t Mylan, Apotex, etc. have been on the market some time ago with an amlodipine maleate? If there is really nothing about amlodipine besylate that is so much better than amlodipine maleate, then why isn’t amlodipine maleate marketed?

    The problem with this CAFC decision is not so much with the fact that the CAFC found a “motivation” — after all, the applicant didn’t argue against the prima facie case but rather rebutted it — but it is moreso that the CAFC went the extra mile and said that none of the secondary considerations were good enough to satisfy the CAFC. The “no reasonable factfinder” language flies in the face of the patent examiner AND three district court judges who had already considered the matter. (Did they ever even state what standard they were using for reviewing the D/Ct’s findings on secondary considerations?)

    The CAFC went so far as to state that EVEN ASSUMING amlodipine besylate demonstrated “unexpectedly superior” results, they would STILL find the invention obvious. Doesn’t there seem to be a problem here?? I am sure there can be unrebuttablle cases of obviousness, but this wasn’t that case.

  8. Measuring Obviousness is like measuring a cloud.

    Is invention a process?, or a spark?, or both?

    How are creativity, inventiveness, obviousness and ordinary-skill-in-the-art, related?

    Some highly educated skilled in the art people can’t create themselves out of a paper bag. This gives rise to an essential patentability question: Does ordinary skill in the art mean: (i) a creative person skilled in the art?, or (ii) merely an educated person skilled in the art?

    Does simple equal obvious?
    What bearing does the perception of an invention being Complex or Simple have? Of course, everything that is simple is not obvious and vice versa. No one suggested simple and obvious were the same, but neither this subject nor any similar notion, which you’d think would of course be an integral part of any serious discussion of obviousness, ever entered the KSR Raccoon-Hearing transcript:
    link to supremecourtus.gov

    What is invention? Invention is what makes the non-obvious obvious: everything is obvious after it has been invented.

    Another problem when testing for obviousness for patentability has to do with the Observer Effect, defined as: “In science, the observer effect refers to changes that the act of observing has on the phenomenon being observed.”

    I.e., Before and After observation: Before observation, Is, is what it is, but after observation, what Was no longer is — before’s Is is gone forever After observation.

    It is, of course, impossible to tell if an invention is obvious before it has been invented — it has not yet been discovered, and thus it does not (yet) exist. And after it has been invented, at least to the extent that invention is what makes the non-obvious obvious, you can no longer tell if an invention was obvious.

    That is why Measuring Obviousness is like measuring a cloud.

    The CAFC’s pragmatic obviousness test, “Teaching, Suggestion, Motivation,” or TSM, is a test that is determined by the presence of some evidence, or the lack of evidence. Of course, there will be on-the-fence cases, and some silly stuff may slip through, but that’s life, and that’s what court’s are for.

    Teaching, Motivation, Suggestion works because TMS is in essence based on some form of identifiable evidence — patentability cannot be likened to measuring a cloud.

    TSM!, because nothing else works.

  9. Keep in mind that for a consumer, taking a pill once a week can be a significant improvement over daily, and so on. And a smooth pill not only goes down easier than a sticky glob, but it can function better too. I’m not saying that tiny changes should allow extension of monopoly, just that improvements can require significant investment and result in significantly enhanced consumer value and appeal. I don’t admire the capitalist system or the consumer-driven economy, but we’re living in one and the patent system is part of it. Innovation is rewarded, but innovation isn’t limited to the big Eureka! For the record, I agree with the decision but I wish they’d left out the sweeping dicta.

  10. “However, when you talk to the inventors (which I do on a daily basis), they “truly” believe that their contributions is a significant inventive step forward.”

    Let’s just say that not all inventors are this romantic.

  11. “patents should be much harder to get for “me too drugs” (i.e., the second, third, fourth and fifth drugs in a particular class).”

    Why? You don’t get cheaper drugs this way. Assuming these “me too” drugs are obvious over the first drug, then there is a strong chance they infringe the first drug patent, preserving its market power. Further, if the me too drugs are not major advances, market power in the first drug is not prolonged by obtaining patents on the me too drugs, because people will just use the first drug when its patent expires instead of using the pricier me too drugs that don’t do much more.

  12. stepback

    An inventor may subjectively believe that his invention is important, he may be genuinely upset when others disagree with him but his feelings are irrelevant to an objective determination of whether he is entitled to government enforced monopoly. We are not running a kindergarten here.

  13. mr,

    I keep hearing these noises about “truly” desrving inventions. However, when you talk to the inventors (which I do on a daily basis), they “truly” believe that their contributions is a significant inventive step forward. They “truly” believe they worked hard to get the idea to its current stage of development. They are “truly” upset when a negativistic naybob shows up in hindsight and after the fact to knock all their work down as being “obvious”.

  14. I find it hard to understand why so many patent lawyers find it necessary to protect the interests of the pharmaceutical industry rather than to maintain independent professional judgment. Obviousness–although now codified by statute, is a judicially crafted doctrine similar to inequitable conduct designed to curb abuses by companies who attempt to wrongly obtain market exclusivity for minor advances in the art that are the subject of mere routine experimentation. We should not reward companies with patents merely because they engage in “grunt work.” Patents should be reserved for truly significant advancements in the art. The next step is for courts to reinvigorate structural obviousness by making it clear that patents should be much harder to get for “me too drugs” (i.e., the second, third, fourth and fifth drugs in a particular class). Companies who try to enter the market by tweaking the structure of a known compound and coming up with something slightly different with little clinically meaningful benefit compared to the prior art compound should not be awarded market exclusivity.

  15. Thomason,

    your worry about courts not being able to decide what is/should be obvious is only a worry if you believe obviousness is a pure matter of law.

    Elsewhere in the world, this is not a concern, since obviousness is a mixture of fact and law, and thus quite properly the preserve of experts. Courts therefore have no hesitation in consulting experts on the matter. In many countries, a large proportion of patent litigation involves experts giving opinions on what they believe the level of common general knowledge in the art to be, and thus what is obvious in light of it.

    But the US seems resitant to going there, no doubt because litigattion in the US is already overly burdened by things the rest of the world doesn’t have to deal with, like the sadly ubiquitous inequitable conduct claims, etc.

    Regards, Luke Ueda-Sarson

  16. 1. It’s quite obvious that the CAFC’s sold out on TSM prior to the Supreme Court’s ruling. Whilst it’s done this, the decision itself is intrinsically problematic. The level of motivation that the Court does apply appears to be a boilerplate phrase ‘and pharmaceutically acceptable salts’ in the prior art amlodipine patent along with Pfizer’s desire to produce a more favorable salt for formulatory reasons. So any boilerplate language must now be the standard for prima facie obviousness as the Pfizer reasoning was internal and not public knowledge! Looks like they’ve opened up another huge can of worms there as well.

    2. I get the impression that the real reason that the Court went this way is because this product has already been before them once before in Pfizer vs Dr Reddy’s. As the Court mentioned on a number of occasions in the decision, you can’t plead in one litigation that there’s no real difference between the 2 salts and then come back and claim superiority later. Whilst they can’t come out and say it, I think that this may actually be their underlying drive to invalidate

    PS a note to Rick – the CAFC has yet to decide the salt selection issues in Lipitor, it favored pushing the debate back 3 years and invalidated on a claim construction issue

  17. I favour John Mortimer’s hero Rumpole. He knew little about the law, but was an expert on bloodstains.

    There was a lot of law in the decision, but eventually, as these cases do, it came down to the fact issues. There seemed to be compelling evidence on the transcript as to lack of inventive step. The court believed the evidence, especially as this was not a drug discovery patent but was an improved formulation patent.

    Interesting as to the way that the court handled the evidence, but not quite a revolution.

  18. Will In Re Deuel stil be good law by the time they finish this? I wouldn’t be so sure…look at In Re Fisher and the way they created a new bar under 101 for DNA inventions…also, what are they going to do with inherency in unpredictable arts…these are all big cans of worms and the way things are going it will be a long time before they are adequately dealt with.

    Couldn’t we solve alot of this patent reform push by leaving 102 and 103 alone and changing what is patentable under 101 (remove DNA ESTs, software, business methods, etc.) and get Microsoft and the rest to leave the rest of the law alone? It seems a better solution than changing 103 to fit Microsoft’s needs and screwing up pharma and biotech in the process.

  19. “I think when you have thousands of possibilities instead of 53, you’re saved by In re Deuel. What cannot be contemplated cannot be obvious, and it’s a lot easier to identify and contemplate 53 than 1000.”

    In some sense however I had to contemplate the combination to program the computer or machine to try it …

  20. “So what happens with automated testing where a computer or a machine is programmed to cycle through thousands or millions of possibilities and happens to find one that works – that’s probably obvious too, no matter how much it might have cost to run the test.”

    I think when you have thousands of possibilities instead of 53, you’re saved by In re Deuel. What cannot be contemplated cannot be obvious, and it’s a lot easier to identify and contemplate 53 than 1000.

  21. Unpredictable arts are unpredictable. That is why so many PhDs become patent lawyers – it is a much easier job.

    As for the case – it is hard for me, a PhD, to determine what experimentation is routine. I have no idea how the courts are going to find any consistent rule on this, but it will be fun to watch…

  22. So what happens with automated testing where a computer or a machine is programmed to cycle through thousands or millions of possibilities and happens to find one that works – that’s probably obvious too, no matter how much it might have cost to run the test.

  23. “All you need is anecdotal facts, paid opinion, cut-and-paste prior art references, and a plausible theory, and the CAFC may declare a patent obvious.”

    Same as it ever was.

    This case was rightly decided and is precisely on point with respect to some of the hypotheticals I provided in the KSR thread. According to the “strict” TSM test (good riddance), it is legally impossible to find a composition obvious when (1) the composition belongs to an “unpredictable art” and (2) every element AND concentration thereof AND a suggestion to combine them is not specifically and expressly found in the art.

    There is absolutely nothing wrong with using “expert” witnesses to provide a clearer picture of the state of the art and what one would try and what one would expect as of the patent’s filing date. I assume that courts will continue to do so for a long time.

    Most of the “new” combinations in pharmaceutical formulations are no less obvious than the “new” varieties of candy bars or energy drinks. Of course, I already have received a notice of allowance for my mango-blueberry-pomegranate-medlar-plantain SooperDooperJuicer(TM) invention.

  24. On further review, the CAFC has sold out a fairly ascertainable standard – that the TSM must be evidenced in arguably-combinable prior art – for a hindsight standard that only the CAFC and paid-experts can apply: “the motivation …is gleaned not only from the prior art as a whole …but also from the nature of the problems encountered ….[incd'g that which] supports an inference that the skilled artisan actually would have been encouraged, rather than discouraged, …[and so] motivated to combine the prior art references.” slip op. pg. 21. Try to apply that “gleaned not only from” standard in your next opinion letter.
    Instead of showing some gumption, and sticking to the TSM standard of express in the prior art, the CAFC goes weenie fearing that the Supreme Court might reverse, and to seek haven from that, the CAFC guts the TSM test and engrafts on a hindsight, who-can-tell, anything is relevant, totality of the, grab-bag measure of TSM. If nothing else, this watered-down test voids the requirement of clear and convincing evidence of obviousness. All you need is anecdotal facts, paid opinion, cut-and-paste prior art references, and a plausible theory, and the CAFC may declare a patent obvious.

  25. Rick: Your comments puzzle me a little. Do you agree or disagree with the result?

    I agree with the court’s result. Too often applicants rely on a lack of teaching, suggestion, or motivation in cited prior art as a response to a obviousness rejection when the teaching, suggestion or motivation was widely known in a particular art; i.e., common knowledge. While this consideration may be difficult for an examiner with limited resources, I suspect that the teaching, suggestion or motivation argument could be the new “inequitable conduct” in litigation, and everyone will immediately assert this argument as part of an affirmative defense (assuming they are not already doing so).

    You can see silliness (as Rick pointed out) in patent applications where an examiner failed to apply a little logic.

    Company A develops and patents a new drug, but the new drug only comes in a glob that is unsuitable for a pill (it dissolves current capsules) and is difficult to deliver in a bottle (too thick).

    Four years after their original patent application the same company applies for a new patent application where the drug is contained by a dissolvable capsule, but the interior of the capsule is coated with a known sugar coating that the company has discovered that the drug will not dissolve (which took chemists a month to discover because they started with the coatings he knew about). A new patent issues because the dual layer capsule is not obvious in light of the prior art, though both the dissolvable capsule and the coating were known, the ingredient in the drug that caused dissolving of the capsule but not the dissolving of the coating was known to do both, and there were no technical hurdles to put one on the other. However, no one ever specifically put the coating onto the capsule (I have heard this in companies before – we knew we could do it, but why?). The drug company has an instant four-year extension on its original patent that will be difficult to overcome because the new capsule is an instant success.

    We can only hope that a more enthusiastic application of obviousness outside of cited art will cause companies to focus more on true innovation rather that trying to squeeze more life out of drug through less sticky tablets.

  26. notwithstanding my comments above about the CAFC jurisprudence, I find it particularly interesting that Pfizer’s Norvasc invention was merely an improvement over the “stickiness” of a prior art tablet.

    The prior art was amlodipine “maleate”. The formulation tablet was too “sitcky”. So Pfizer invented amlodipine “besylate”, which proved to be less sticky.

    The benefit too consumers: a less sticky tablet for a price increase of about 5,000%..

    What an absurd system…

  27. so the Federal Circuit is trying to save its face in anticipation of an embarrassing KSR reversal at the Supreme Court…

    This is just plain pathetic..

    Anyone familiar with the Lipitor and Plavix cases, would readily realize that this court has taken a 180 degree u-turn in its obviousness jurisprudence (Plavix was about selecting a salt from about 50 salts – Lipitor was about selecting an enantiomer from a racemate – both cases held nonobvious).

    Judge Linn concurs with the result – but provides no opinion. (probably unsure what the law is, but his gut feeling tells him the result is correct.)

    The WOBBLY Federal Circuit at its best…

Comments are closed.