by Dennis Crouch
Documents: FedCir Vanda Decision; Vanda EnBanc Brief
The Federal Circuit recently sided with the accused infringers Teva and Apotex, affirming the invalidation claims from four Vanda patents covering methods of using tasimelteon to treat circadian rhythm disorders. However, the patent owner has petitioned the court for en banc rehearing, arguing the panel improperly disregarded evidence of nonobviousness. Responsive briefing from the generics are due on August 1.
This case provides an interesting look at the application of the obviousness standard to pharmaceutical treatment methods.
Background: Vanda Pharmaceuticals owns patents covering use of the drug tasimelteon to treat Non-24-Hour Sleep-Wake Disorder (Non-24), a condition caused by lack of synchronization between a person’s circadian rhythm and the 24-hour day. Tasimelteon is sold under the brand name Hetlioz and has over $100m in annual sales. Several generic drug makers, including Teva and Apotex, filed Abbreviated New Drug Applications (ANDAs) with the FDA seeking to market generic versions of tasimelteon and with allegations. Vanda sued, alleging infringement of four patents that were listed in the Orange Book. RE46604 (Claim 3); US10149829 (Claim 14); US9730910 (Claim 4); US10376487 (Claim 5). The district court found all asserted claims obvious based on prior art teachings about tasimelteon and related drugs. Vanda appealed.
In a May 2023 decision, the Federal Circuit affirmed the invalidity ruling. The panel found no error in the district court’s determination that the prior art would have provided a reasonable expectation of success for the claimed inventions.
Key Aspects of the Federal Circuit’s Obviousness Analysis
The inventions here involved fairly narrow differences, and the Federal Circuit concluded that a PHOSITA would have seen a reasonable expectation of success:
- Administering without food: There was a motivation to try and a reasonable expectation of success here since FDA guidance recommended food studies, and there are just two potential options (with or without food). There result here is close to a per-se obviousness ruling.
- 20 mg dose to “entrain patients”: The prior art disclosed 20 mg dose and suggested entrainment. Still obvious even though the prior study results (Rajaratnam) were not statistically significant. In a different patent application, Vanda had characterized Rajaratnam as showing that an oral dose of 20 mg was effective. The court also noted that an ongoing clinical trial at the time was testing 20 mg — further contributed to the expectation of success.
- Avoiding Co-administration with CYP enzyme inhibitors: A similar drug (ramelton) had shown problems with co-administration with these CYP enzyme inhibitors, creating a reasonable expectation that tasimelteon would also show similar results. On this point, the testimony was that PHOSITA would not have “ruled out an interaction.”
The key with all of these is reliance on KSR‘s flexible approach and expanded use of the reasonable expectation of success standard. Although Vanda argued objective indicia, it was given very little consideration by the appellate panel.
Vanda’s Petition for Rehearing En Banc
Vanda’s en banc brief asks three questions:
- With or Without Food: Whether method-of-treatment patents directed to the effect of food on a particular drug are per se obvious because of FDA Guidance acknowledging that food may affect the bioavailability of drugs and should be studied.
- Clinical Trial as Evidence of Reasonable Expectation of Success: Whether a disclosure showing existence of an ongoing clinical trial is evidence of a reasonable expectation of success as to the result of the trial. See OSI Pharms v. Apotex (Fed. Cir. 2019) (clinical trial provides only hope, not expectation of success).
- Results from Similar Drug: Whether a drug-drug interaction patent is obvious when a POSA could not “rule out” the interaction because another compound in the same general category has shown such an interaction.
The petition urges the full Federal Circuit court to take the case en banc to maintain uniformity of obviousness precedents. I’m sure that companies in the life sciences sector will be closely watching this case as it continues to unfold.
The key question is the meaning of “reasonable” in the “reasonable expectation of success” when dealing with clinical trials. Phase I clinical trials are not about efficacy. They are usually about safety and dosing and conducted with healthy volunteers. Thus, assumptions of efficacy heading into Phase II are unwarranted. However, Phase II clinical trials are about efficacy. Without efficacy in patients under real world conditions, development ends. Would a company initiate Phase III trials unless the Phase II trials were successful? Method claims based on the results of Phase III data would then be more likely to have a “reasonable” expectation of success because it was already known that there was both efficacy and safety in the tested drug. Whereas, method claims based on preclinical or Phase I data are much less likely to have a “reasonable expectation of success.”
Rather than looking at the overall success rate of drugs that enter all clinical trials, I would look at the success rate (meaning FDA final approval) of drugs that enter Phase II trials. The percentage of drugs that go from Phase II to approval is much much higher than those that go from Phase I to approval. Considering that efficacy is only properly evaluated beginning at Phase II, this is a much better time point in which to evaluate the reasonable expectation of success.
The Prophet’s claim was that the fact that clinical trials are moving forward is enough to find a reasonable expectation of success.
Regardless, only about 30% of the drugs in Phase II are successful.
How many of those 70% have claimed utility that simply is not there?
“ The Prophet’s claim was that the fact that clinical trials are moving forward is enough to find a reasonable expectation of success.”
Not just me. See the quote from the American Cancer Society in my earlier comment.
And to be crystal clear: the existence of a clinical trial relating to process X is not BY ITSELF conclusive that process X has a legally sufficient “reasonable expectation of success.” But it certainly is evidence to be considered in support of that conclusion.
The ACS quote (AND article) do not say what you appear to think that they say, Malcolm.
I ‘get’ that you want to pivot to ‘success’ at the expense of ‘expectation,’ but you appear to not even understand the different aims of the different phases of clinical trials — and critically — what exactly is at stake with claimed utility of (most all) Pharma patents.
Bottom line is that the claimed utility is simply (most all) NOT possessed at time of filing, and that this is shown quite explicitly in the drop out rate from the FDA trials.
Of the provided 70% of items that
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100% of those items do not have the ‘success’ that you want to pivot to.
“Method claims based on the results of…”
That’s just it: most all Pharma patents simply do NOT have ANY claims so “based on,” as the claims are typically written well before the FDA process is engaged.
That is one of the long-running beefs about Pharma and their patenting practices, as possession (for ALL art units) of things like utility is required at time of filing.
It’s not a “study plan” and a “maybe this will work” plan.
And this decision is exactly why pharma “claims early” (to paraphrase your words). It appears that the arguments are that a claim does not have utility unless one has PhII results, but at the same time, prior to the PhII results, such a claim would be obvious to try?
“but at the same time, prior to the PhII results, such a claim would be obvious to try?”
That has never been a position of mine.
As such, it is unclear to me what point you are trying to make.
Further, “And this decision is exactly why… ‘claims early’…” is NOT permissible under patent law.
NO art unit enjoys that privilege.
One must possess the claimed utility at the time of filing.
Period.
We have incontrovertible evidence to the contrary – and not in some small degree.
Fact pattern: There is a transgenic human mouse model of a human disease. This transgenic mouse produces a mutated form of a human protein and exhibits all symptoms of human disease (similar to what is observed in human patients who have the same mutated gene/disease). Pharma creates a small molecule that fixes the mouse. No human trials have yet been started.
q? At this point, would one have possession/utility to a method of treating a human claim with the small molecule?
Would the Person Having Ordinary Skill In The Art recognize a claimed “therapeutically effective” claim term – outside of an actual passing of a proper FDA result?
I ‘get’ you want to grease the slope with ‘transgenic.’ But is that enough?
Would ANY such Pharma be happy with — after your established fact pattern — obtaining a claim expressly to the mouse situation? (for which possession could be established)
“ The key question is the meaning of “reasonable” in the “reasonable expectation of success” when dealing with clinical trials.”
I disagree. The key question as it relates to the patent system is the definition of “success.”
“Phase I clinical trials are not about efficacy. They are usually about safety and dosing and conducted with healthy volunteers.”
Does the FDA approve phase I trials without evidence demonstrating that the therapy is likely to have a beneficial effect?
Prophet – your questions run into the intersection and differences between the requirements to receive a patent and the requirements to receive FDA approval to market a drug. “Success” in terms of a patent can mean simply inhibiting an enzyme or producing a small therapeutic effect while there is a huge difference with the FDA. As for a beneficial effect – your question is somewhat of a red herring because no company is going to spend the hundreds of millions of dollars (or more) to bring a drug to market unless there is some sort of effect that can be marketed to patients and doctors. For follow-on drugs (same therapeutic effect as a previously approved drug), it has to be at least as good as, but often better, than the previously approved drug. The differences between what the FDA requires and what the USPTO requires is huge and definitely subject to scrutiny from many different directions.
“”Success” in terms of a patent can mean simply inhibiting an enzyme or producing a small therapeutic effect while there is a huge difference with the FDA.”
Right. But my point is that a “successful” clinical trial requires a LOT more than the kind of “success” required by the patent system. Clinical trials are not even initiated unless there is already a reason to believe that the drug will be effective. And it’s for this reason that the existence of a clinical trial can and SHOULD BE considered evidence in support of a “reasonable expectation of success” of a patent claim directed to similar subject matter. It need not be outcome determinative evidence, and the devil is in the details, but it still should be considered as evidence.
“more than the kind of “success” required by the patent system”
You appear to NOT understand what the patent system requires.
It is not “study plan for a chance at possession.”
It IS possession — at the time of filing — of the claimed innovation.
This is not difficult, and for one such as you that so ardently would deny innovation protection to a VAST swath of the innovations of the fifth Kondratiev to so ardently get this wr0ng raises a serious question as to your objectivity.
“The differences between what the FDA requires and what the USPTO requires is huge”
Your blanket statement is (of course) false.
For example, in the immediate context, the claim language clearly sets the standard to be one and the same.
Big Pharma is perfectly knowledgeable about how to write a claim to something that there need be no FDA approval.
Of course, such a claim would not be very valuable.
They are called clinical “trials” not clinical confirmations. One out of 10 drugs does not make it through Phase 3. Is that a reasonable expectation of success?
A 2018 publication reports that probability of success depends on the drug and runs from 3.4 (cancer) to 33.4 (vaccines), for an overall rate of 13.8 or 20.9 (if oncology is excluded).
As for food, which foods? Just any food? Not a binary inquiry. Some drugs are to be taken with food to prevent stomach discomfort. That is binary.
Other drugs cannot be taken with certain foods. For example, grapefruit can increase the effectiveness of certain drugs and, thus, side effects — e.g., statins (cholesterol), calcium channel blocker (treat high bp), estrogen. For some drugs, like Allegra, grapefruit decreases its effectiveness. But, I guess that is all obvious.
From the American Cancer Society website: “Clinical trials are done only after pre-clinical findings suggest that the new drug or treatment is likely to be safe and will work in people.”
link to cancer.org
Did we not just have a lengthy lesson here last month explaining the many sound reasons that the standards for patentability of “effective” drugs and treatment methods are far LESS restrictive than the standards for obtaining FDA drug approval? And that the patent standards are only heightened to FDA levels when the claims recite limitations that accord with FDA approval requirements?
Depending on the prior art, drug treatment claims need not be limited to humans. They need not rely on any human data if there is data showing efficacy on a recognized animal model.
Again: the relevance of a clinical trial to a claim is dependent on exactly what is being claimed (and what’s in the trial) which is why it is silly to proclaim across the board that a clinical trial is evidence only of “hope” for “success.”
The claims – then – should include that reference to animals as opposed to (what we recently covered) was to a term recognized by Persons Having Ordinary Skill In The Art to be to the FDA standard.
Pay attention son.
Nobody pays attention to your gibberish except to mock you.
Well, there is your first mistake.
One does not need to show clinical trial success to prove enablement. But, one will not be able to practice the claimed method without FDA approval.
Are you saying that, because one does not need to show clinical trial success to prove enablement, the probability of success of clinical trials should not be considered for obviousness?
“ Are you saying that, because one does not need to show clinical trial success to prove enablement, the probability of success of clinical trials should not be considered for obviousness?”
I’m saying that, in light of the fact that clinical trials on humans are not conducted UNLESS it is deemed likely that a drug will be effective, the fact of an ongoing clinical trial can be evidence that an expectation of effectiveness (“success”) is reasonable. Again, this all hinges on what exactly is recited in the claims and what is going on in the trial.
“he fact that clinical trials on humans are not conducted UNLESS it is deemed likely that a drug will be effective,”
Tell me again (or to be more precise – for the first time), just how many clinical trials do NOT end up meeting the (claimed) stated FDA levels of ‘therapeutically effective‘ (and the like)
But hey, you continue to be you, Malcolm.
“one will not be able to practice the claimed method without FDA approval.”
Indeed. And FDA approval is not contingent on the existence of a patent because the standards are different (and rightly so).
News just in, apparently some support for the new supposed “superconductor RT”.
link to twitter.com
Still rumor tier, still 99.999% likely to be wrong, but there is a glimmer, simulated.
Appears that it is less news and more mere regurge.
Also, has not been replicated in the decade or so since the original experiment was done.
See Zeihan’s synopsis at: link to youtu.be
Why is it always the pharma cases?
always….?
Okay, maybe there was some hyperbole there…
That question as to why pharma patent cases seem to get all the reported appellate efforts has the same answer as was given years ago by a famous bank robber about his activities: “Because that’s where the money is.”
The claims are everything and I suspect (without seeing them) that Vanda is reading a lot more into the claims than is there.
The existence of an FDA-approved clinical trial would seem to be GREAT evidence of a “reasonable expectation of success” for effectiveness of a drug. The question then is whether the claims require more and what exactly do the claims require. Some vague “limitation” regarding “food” wouldn’t seem to matter for squat unless there is a clear teaching in the art relating to this compound and food. And by “clear teaching” I don’t mean one obscure reference mentioning something that is cited nowhere else among the hundreds of other references discussing the drug.
“The claims are everything and I suspect (without seeing them) that”
¯\_(ツ)_/¯
Your opinion does not even accord your assertion.
If indeed “everything,” then you would not venture a knowingly uninformed opinion — without at least having a bare reading of the claims.
“The existence of an FDA-approved clinical trial would seem to be GREAT evidence of a “reasonable expectation of success”
Putting your feelings aside, may I suggest that you grow up and look at the sheer number of items that do NOT pass FDA clinical trials.
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