Appellate Panel Upholds Forest's Lexapro Patent

Forest Labs v. IVAX (TEVA) and CIPLA (Fed. Cir. 2007).

The Court of Appeals for the Federal Circuit today upheld Forest Labs patent on its billion dollar SSRI Lexapro (escitalopram oxalate) — rejecting IVAX’s arguments that the patent is anticipated and obvious. Based on two FDA extensions, the patent is set to expire on March 14, 2012.

This case is an important stepping stone in our new understanding of obviousness.  Interestingly, in its multi-page discussion of obviousness, the appellate panel did not mention the Supreme Court’s recent landmark decision of KSR v. Teleflex. 

History: Forest holds an expired patent on a racemic form of citalopram. After considerable effort, Forest’s scientists doubled the strength of the drug by isolating the (+) stereoisomer (which turned out to be the only active isomer) and patented that isomer in a “substantially pure” form.  A prior art pharmacologic paper had suggested that the (-) stereoisomer would be the potent isomer, but that reference did not describe the preparation of the enantiomer.

Anticipation and Obviousness: The prior art reference (Smith) suggested isolation of a stereoisomer to create a more potent drug. That reference, however, did not enalbe the process of isolation. As we know, “[a] reference that is not enabling is not anticipating.” Similarly, for obviousness, the difficulty in isolating the steroisomer without undue experimentation along with other secondary factors led the court to the conclusion of nonobviousness.

At this point, the court could have explicitly distinguished this case from KSR v. Teleflex. Under KSR, knowledge of one stereoisomer would likely make the other stereoisomer obvious. (A simple variation requiring little creativity.)  Based on the Smith reference, it would be obvious to consider creating a substantially pure form of escitalopram.  However, KSR requires more than an obvious variation — It also requires the ability to implement that variation.

If a person of ordinary skill in the art can implement a predictable variation, and would see the benefit of doing so, §103 likely bars its patentability.

In the case of Lexapro, the facts indicated that a person of ordinary skill in the art could not implement the variation without a large amount of uncertainty and experimentation. Nonobviousness affirmed.

Appellate Practice: Most non-patent appeals typically focus on errors made by the lower court. Most patent cases, however, involve questions of law that are reviewed de novo (such as claim construction). Appeal of those issues do not require the appellant to show that the lower court was “wrong.” Instead, the appellate panel must simply be convinced of a better way. 

In this case, the majority opinion chastizes IVAX on several occasions for its implicit arguments for de novo review of the factual decisions of the lower court. Those decisions are instead reviewed for clear error – a much higher standard.

[T]heir arguments … are largely a recounting of the testimony favorable to their theory of the case without explanation as to why we should have a definite and firm conviction that mistakes were made by the district court in its fact-finding. In other words, they do not inform us why the district court was not entitled to rely on the evidence favorable to Forest or demonstrate that the evidence favorable to them heavily outweighed the evidence favorable to Forest.

Discussion of Injunction in Subsequent Post

Notes:

• Hal Wegner has indicated that this case should be of interest for those following the recent Plavix appeal.

Comments

[dr2chase]

I suppose I should read the decision AND get out my legalese-decoder ring, but this lapsed electrical engineer knows that biologically active chemicals come in stereoisomers, and it's no news to him that the two isomers can have radically different effects (working/not, working/poison).

I know that if I had a new drug, I would assume it had stereoisomers, and assume they would have different effects, and would set about isolating them for further testing. I sure hope that there is more to this patent than just that.

[jimbob]

Multi-page discussion of obviousness?? Did we read the same opinion?

The obviousness section is less than two (2) pages.

[David Jaglowski]

"[The Smith reference] in effect does state that there is a (+)-enantiomer of citalopram, but it does not tell how to obtain it. A reference that is not enabling is not anticipating." Slip op. at p. 8.

Unless you can show a combination of references that teach how to resolve the claimed enantiomer, your desire to isolate the enantionmer is not significant. Pages 4, 5, and 9 of the opinion show that there is substantially more to the patent than just that.

[ohmy]

Crouch: "Under KSR knowledge of one stereoisomer would certainly make the other stereoisomer obvious."

Huh? From my reading, KSR had nothing to do with stereochemistry. That's quite a leap!

[KCB]

Look ohmy:
The patent system is designed for intellectuals. I find it quite amusing these off-the-cuff opinions by neophytes such as Dudas and the Supreme Court on matters of far too much complexity and nuance for them to fully grasp. What is really amusing are law professors who spend three years writing 20 patent applications and think they know it all.

[Kevin E. Noonan]

dr2chase:

Your post nicely illustrates the inherent differences between electrical engineering and chemistry. There is no way to assume there is function-related stereochemistry for a drug, even if there is indeed stereochemistry in the molecule. The patent claim at issue is a "substantially pure" preparation of one enantiomer, something that the evidence clearly showed was non-trivial to obtain. The combination of 1) unpredictable that one (and which one) of the isomers would have better activity and 2) the lack of expectation of success in obtaining it were the keys to patentability.

[MaxDrei]

There's a way to reconcile the common sense of engineers with the sensibilities of chemical patent attorneys, when it comes to obviousness of stereoisomers. See the English Lundbeck decision published a few weeks ago. There, the isomer was a research target but there was invention in isolating it. What the inventor got from the court was: Claim to the isolated isomer (howsoever obtained) not obvious, but nevertheless bad for insufficiency (cf Leibel-Flarsheim?). Claim to the clever isolation method held good. That way, inventor gets protection, of a scope commensurate with his contribution to the world's store of technical knowledge.

[Chemical Guy]

Absolutely correct decision, though Schall's dissent, strictly speaking, is probably correct in its reading of the statute re Cipla's culpability under 271(e). I wonder if Moore and the others who recently denied rehearing en banc in the amlodipine besylate case (Pfizer v Apotex, where the besylate salt was ruled obvious) will grant rehearing on this one so they can overturn the panel and continue to make bad law. (Curiously, Schall, who voted to deny rehearing in Pfizer, agreed in the present case that the patent was not invalid for obviousness. Friedman, also on the present panel, didn't participate in the rehearing decision in Pfizer and Lourie, the author of the present decision, voted in favor of rehearing.)

[Tufty]

The decision on validity is clearly wrong. If the idea of the single enantiomer was obvious, given that the racemic mixture was known, then it should not be possible to claim the enantionmer by itself, regardless of whether it was possible before the priority date to make it. The actual invention in this case lay in how to separate the enantiomers, not the idea of which one would be better. The patentee should therefore have only been allowed a method claim on how to do it. The corresponding decision in the UK got it right (see http://ipkitten.blogspot.com/2007/05/lundbeck-lose-cipralex-protection.html).

(sorry to repeat myself; something up with the comment facility not letting me post on this one earlier)

[Jud]

Tufty,
For a patent to be invalidated by a prior reference, the prior reference must be enabling. This reference was not. Is that so hard to see?

[Malcolm Mooney]

"For a patent to be invalidated by a prior reference, the prior reference must be enabling. This reference was not."

Remember that the standard for enablement of an anticipatory prior art reference is lower than required for patentability.

The crucial facts in this case are that isolation of a pure (-) stereoisomer does not equate with the isolation of a pure (+)stereoisomer, and that the patentee was able to marshall qualified, competent and credible experts (at least versus the defendant) to testify that, as of the filing date, one could not have reasonably expected to successfully isolate the (+) stereoisomer.

As I write that, I find myself asking: are there any enantiomers of compounds of similar complexity to Lexapro that have notoriously resisted all attempts of modern chemists to separate them? Or is it in fact the case in 2007 that one reasonably expects that ANY racemic mixture of moderately complex chemicals can be separated into its enatiomers given a couple years of diligent work?

[Malcolm Mooney]

Over at Patent Docs, Noonan writes

"Finally, the District Court found that claim 11 was not invalid for being impermissibly broadened more than two years after the patent issued. In reissue, claim 11 was amended to recite that a (-)diol intermediate was converted to (+)citalopram; the claim as issued recited that (+)citalopram was produced from a (+)diol intermediate. The District Court found that the error was merely a typographical error, and would have been appreciated by a worker of ordinary skill."

http://www.patentdocs.us/patent_docs/2007/09/forest-labs-inc.html

Merely a typo?? Did the patentee not have the opportunity to fix that alleged "typo"?? Is this a knife stabbed into CHEF AMERICA's back?????

[Tufty]

Jud,

The reference does not have to be enabling to make one or the other enantiomer an obvious goal, even though achieving it might be difficult. Claim 1 of the patent is to the enantiomer in a 'substantially pure' form. It is enabled, because the patent shows one way of making it. It is, however, not inventive over the racemic mixture. The process of how to get there may well be inventive, but that is a different story.

By the way, the test for a prior reference to be enabling is about novelty, not obviousness. Are you a US patent attorney or something?

[metoo]

Enablement is indeed relevant to the question of obviousness, at least under US law. See, e.g., In re Kumar and In re Payne ("the presumption of obviousness based on close structural similarity is overcome where the prior art does not disclose or render obvious a method for making the claimed compound").

[dr2chase]

I guess it depends upon what you mean by "assume". Thalidomide, Naproxen Sodium, and sugar all have differently-behaving stereoisomers. It may be that the stereoisomers of a drug behave identically, but it's a good bet that they don't. I may not know it with certainty until I isolate the stereoisomers and test them, but I am not going to be surprised by a positive result. In English (a distinct language from what is spoken in patent law) an unsurprising result is regarded as obvious, or near to it.

Now it could be that separating/producing the stereoisomers in commercial quantities is an interesting problem with a non-obvious solution.

[Kevin E. Noonan]

Malcolm:

The case doesn't make it clear, but I can envision the following scenario:

Since the change impacted the structure of the compound, the patent had to be reissued to correct it.

But the stereochemistry was such that a chemist would have recognized that the chemical structure described was (+) instead of (-), so it is something of a typo (because the skilled worker would have recognized it as suhc).

Just a thought.

[Lexapro Prescription Medication]

My name is Lucas Sneed and i would like to show you my personal experience with Lexapro.

I am 39 years old. Have been on Lexapro for 3 years now. Went through a phase in life where I lost my job and was under-employed for a couple of years. Had descended to an all time low in self-loathing. Doc intially placed me on Welbutrine, which made me un-motived and essentially a disinterested by-stander in the story that is my life. Switched me over to 10mg dose of Lexapro, which has never increased. I now have a job I love (OK, like) and do not worry about the future. I continue to take Lexapro, as I said I am not as easy going if I miss several doses. My wife can tell when I am off of it, as little things will drive me nuts: barking dogs, annoying habits of others, other drivers, belligerent children...the usual list of suspects. My mother's side of the family is full of passionate, emotional rage machines, so it is a genetic thing or I am a product of the environment in which I spent my formative years. When I am on it I am calm cool and in control. Have notfound it to be physically addictive nor experienced any side effects.

I have experienced some of these side effects-
Uneven temperment, lack of patience if I skip several doses.

I hope this information will be useful to others,
Lucas Sneed