By Chris Holman
Salix Pharms., Ltd. v. Norwich Pharms. Inc., 2024 WL 1561195 (Fed. Cir. Apr. 11, 2024)
Human clinical trials play an essential role in the discovery, development, and regulatory approval of innovative drugs, and federal law mandates the public disclosure of these trials. Pharmaceutical innovators are voicing concern that these disclosures are increasingly being used as prior art to invalidate patents arising out of, or otherwise relating to, these trials, in a manner that threatens to disincentivize investment in pharmaceutical innovation. A recent Federal Circuit decision, Salix Pharms., Ltd. v. Norwich Pharms. Inc., illustrates the concern. In Salix, a divided panel upheld a district court decision to invalidate pharmaceutical method of treatment claims for obviousness based on a clinical study protocol published on the ClinicalTrials.gov. website. The case garnered amicus curiae briefs filed by several innovative pharmaceutical companies in support of the patent owner, Salix Pharmaceuticals.
The case involves multiple patents relating to the antibiotic rifaximin, including patents directed towards methods for treating hepatic encephalopathy (“HE”) and polymorph patents. The relevant patents, for the purposes of this blogpost, are directed toward methods for treating irritable bowel syndrome with diarrhea (“IBS-D”) by administering 550 mg rifaximin thrice-daily (1,650 mg/day), for 14 days (“the IBS-D patents”).
Following a bench trial, a district court held the asserted claims of the IBS-D patents to be obvious over two primary prior art references: (1) a clinical trial protocol that had been published on the ClinicalTrials.gov website (“the Protocol”), and (2) a journal article (“Pimentel”). The Protocol provides an outline of a planned Phase II clinical trial evaluating twice-daily doses of 550 mg (1,100 mg/day) and 1,100 mg (2,200 mg/day) for 14 and 28 days for the treatment of IBS-D. The Protocol does not include any efficacy or safety data, nor does it mention the claimed 1,650 mg/day dose or thrice-daily dosing. Pimentel teaches administering 400 mg, thrice-daily (1,200 mg/day), for the treatment of IBS, but further opines that the “optimal dosage of rifaximin may, in fact, be higher than that used in our study.” (The court assumed no meaningful distinction between IBS and IBS-D.)
The district court found that the two references disclose each and every limitation of the challenged IBS-D claims, and further found that a skilled artisan would have been motivated to combine those two references to arrive at the claimed methods with a reasonable expectation of success. The court then concluded that the challenged IBS-D claims were invalid as obvious.
Salix appealed, arguing that even if the asserted combination of references effectively discloses the claimed 1,650 mg/day dosage, there was insufficient evidence to support a finding of a reasonable expectation of success in using that particular dosage amount.
Vanda Pharmaceuticals, which describes itself as a pharmaceutical company that “specializes in acquiring compounds that other companies failed to develop into a useful treatment and, through costly and time-consuming clinical studies, finding novel uses for them in treating patients,” filed an amicus curiae brief with the Federal Circuit in support of Salix, arguing that, “properly construed, the patent laws do not establish the mere disclosure of ongoing clinical trials—and, in particular, postings on ClinicalTrials.gov—inform a person of ordinary skill in the art (POSA) about the reasonable likelihood of success in the future, and thus this is no basis to hold a patent invalid.” Vanda points out that Federal law requires the sponsor of a study to disclose the trial to the National Institutes of Health, which by law must promptly report information about the study publicly on ClinicalTrials.gov. Failure to publicly report an ongoing clinical trial is, Vanda states, “grounds for criminal liability, including imprisonment and financial penalties, as well as hefty civil fines.”
In its brief, Vanda argues that:
clinical trials are far from a sure thing – indeed, most drug trials fail. [M]erely describing the design of an experiment in a ClinicalTrial.Gov disclosure tells a POSA nothing about the obviousness of the study’s eventual result. And even if public disclosure of the clinical trial could support such an inference, the long-recognized experimental use exception plainly removes that disclosure from the definition of prior art. The Court has recognized that a clinical study itself is a protected experimental use of the invention. The same result must follow for the public, involuntary disclosure of the existence of the study on a government website. Any other rule—one requiring innovators to hand over their valuable intellectual property in service of the government’s public policy ends—would not only defy statutory text, constitutional principles, and settled precedent but smother innovation that produces lifesaving therapies.
Vanda points to its own recent experiences in the case of Vanda Pharms. Inc. v. Teva Pharms. USA, Inc., 2023 WL 3335538 (Fed. Cir. May 10, 2023), in which Vanda’s patent on a method of using tasimelteon to treat Non-24-Hour Sleep-Wake Disorder was invalidated for obviousness, based in part on the companies compelled public disclosure of the existence of a then-ongoing phase III clinical trial of tasimelteon in Non-24 patients. Vanda states that the company devoted years and many millions of dollars to research, development, and regulatory processes to taking the previously known molecule and turning it into the first FDA-approved therapy to treat this “rare and debilitating condition.” Vanda goes on to contend that simply knowing about a clinical study while it is still ongoing cannot create a reasonable expectation of success in a highly unpredictable art such as drug development, pointing to statistics showing that only about a third of drugs move from a Phase II study to Phase III, with only about 12% of drugs that enter clinical trials ultimately achieving FDA approval.
Regeneron Pharmaceuticals and Ocular Therapeutix teamed up to file their own amici curiae brief in support of Salix, in which they attributed the increasing use of clinical trial protocol summary disclosures as evidence of a “reasonable expectation of success” in the obviousness analysis to the enactment in 2007 of the Food and Drug Administration Amendments Act, which greatly expanded the number of trials requiring disclosure, which was exacerbated by regulations put into effect by the Department of Health and Human Services in 2017 that further expanded the disclosure requirements. Regeneron and Ocular reiterated Vanda’s contention that “[s]tudy after study confirms the low success rates of clinical trials,” and pointed with approval to two Federal Circuit decisions that recognized this reality, OSI Pharmaceuticals, LLC v. Apotex Inc., 939 F.3d 1375 (Fed. Cir. 2019) and Novartis Pharmaceuticals Corp. v. West-Ward Pharmaceuticals International, Ltd., 923 F.3d 1051 (Fed. Cir. 2019).
The Regeneron/Ocular brief states that the problem is not limited to the courts, and that mandated clinicaltrials.gov disclosures are now being used as evidence of obviousness in IPR proceedings and during patent examination. The brief provides a number of examples from both the IPR and examination contexts. It goes on to warn that the current trend of using clinical trial protocol summaries as evidence of obviousness is discouraging investment in pharmaceutical innovation and pressuring researchers to file patent applications too early in the drug discovery process.
The Federal Circuit panel majority was not persuaded, however, and affirmed the district court’s decision. It observed that although it was “hesitant to conclude as a general matter that the disclosure of a Phase II clinical trial plan, standing alone, provides an expectation of success sufficient to render obvious a dosage that was not included within the planned clinical trial[, in this case] the Protocol was not asserted alone; it was asserted in combination with Pimentel.” The court further explained that:
The district court did not clearly err in finding that a skilled artisan would have looked to both of those references, considered their limits, and had a reasonable expectation of success as to the efficacy of 550 mg TID dosing. The combined message that the skilled artisan would have discerned from the Protocol and Pimentel is that the optimal dosage for treating patients suffering from IBS disorders may be higher than 400 mg TID, and the next higher dosage unit from the Protocol was 550 mg. We see no clear error in the conclusion that there would have been a reasonable expectation of success in administering the claimed 1,650 mg/day to IBS-D patients. Indeed, certainty and absolute predictability are not required to establish a reasonable expectation of success.
Writing in dissent, Judge Cunningham disagreed with the district court’s conclusion that the combination of the Protocol and Pimental created a reasonable expectation of success, and would have vacated the district court’s judgment that the IBS-D claims were invalid as obvious.
While the generic challenger prevailed with respect to the IBS-D patents, the district court found the patents directed toward the use of rifaximin to treat HE to be infringed and not invalid, and ordered that the effective date of a final approval of Norwich’s ANDA should not precede October 2029, which is the latest expiration date associated with the HE patents. The panel unanimously affirmed this
Question to the board. How does one not prior art themselves (via CT.gov forced disclosures), but enable a claim to: “A method of treating a human subject diagnosed with big toe disease comprising administering a therapeutically effective amount of Drug X.”
Generally curious.
I am also looking forward to any (meaningful) discussions or suggestions from others on this point.
Perhaps Greg should have been spending more time on this topic as opposed to his Kool-Aid swigging?
How odd – not a peep from Greg, and Pharma is his backyard.
Additionally, while you can redact a lot of information for CTG (such as actual dose or dosing schedules), the new CTIS/EMA rules require a lot more disclosure and will be a significant source of prior art moving forward. So patent strategies will be different if your company is doing clinical trials in Europe first.
Yes, all of the pharmaceutical companies are on the verge of bankruptcy because of the broken patent system.
Actually, Pharma doesn’t need patents. They have Cooperative Marketing Agreements (CMAs) where they divide the markets among themselves. And there are “Strategic Alliances”. See link to worldpharmatoday.com
CMAs and Strategic Alliances used to be called illegal monopolies and companies were prosecuted for doing it. Not any more.
And Pharma is free to bribe doctors. See link to propublica.org
That is why Pharma can charge whatever they want for their drugs, even drugs whose patents expired decades ago.
That is why they don’t need patents. If they did they could have all of the politicians they own “fix” the patent system for them. See link to statnews.com
Yes, I really feel sorry for Big Pharma.
As Mr. James points out, the “solution” to this alleged problem is well-known: file a patent application before you submit the clinical trial protocols. The complaints above have been heard before and they are red herrings. FDA approval hinges on other factors that aren’t necessary for obtaining a patent; as a result, citing the difficulty in obtaining FDA approval is irrelevant to the question as to the expectation of success in obtaining THE CLAIMED METHOD. What competent practitioner recites a limitation “wherein the drug is FDA approved” in their claimed method?
Words like “effective” and others are equivalent.
This is not a new concept.
As if pharma companies don’t already file (to the extent possible) before disclosing anything to the FDA. You must be proud that you were the first to figure that out, Mooney.
But sometimes – gosh, the molecule is know but not yet approved for anything, or is approved for something else, and it’s gonna take full-blown clinical trials to get approval, and writing a patent application that guesses about the specific treatment regimen isn’t good enough to get a patent. Or the FDA may demand so much that clinical trials will take so long it’s not worth developing the thing.
There’s a phase difference between the patent cycle and the FDA approval cycle, and it works against pharmaceutical innovators. Using patent applicants’ own FDA protocols against them is a sure way to reduce the number of approvals of new uses, or first approvals of known but previously unapproved compounds.
Poetic justice would be for Mooney to contract a form of cancer that doesn’t have a treatment available b/c insufficient patent protection was available for the molecule or treatment regimen proposed thanks the kind of “reasoning” shown by Judges Lourie and Chen.
The old dichotomy — what will be enough to render your claims invalid would not be enough to enable your claims — can work to one’s detriment for method of treatment claims.
Study plans are not the proper subject of patent applications (hence, possession AT the time of filing is required).
I could agree with you if the CT.gov posting would not be considered prior art.
You can’t even claims its the inventor’s own disclosure if you are lucky to have results within a year. There is no “author” in a CT.gov posting so there is no way for an Examiner to see that the disclosure was by an inventor….
Rock meet hard place.
“Rock meet hard place.”
Correct.
I know that this will be little solace, but as we have had prior discussions on this (and — yet again — my past points are proving to be true), the plain facts of the matter are that Big Pharma will be caught between that rock and that hard place, unless the government does something to change the law.
You simply have a real problem with patent law as written, seeing as possession is a must at time of filing, AND wanting claims to cover any human-approved use.
“ Poetic justice would be for Mooney to contract a form of cancer that doesn’t have a treatment available b/c insufficient patent protection was available for the molecule or treatment regimen”
You people are so effin silly sometimes I can’t even.
“Silly” is not the word I would use for wishing cancer on someone (even you).
Despicable.
It is not clear to me that the clinical trials were the patentee’s.
“Norwich challenged the IBS-D claims’ validity by asserting as prior art references a clinical trial protocol that had been published on the ClinicalTrials.gov website in 2005 (“the Protocol”)1 “
Once upon a time, the CAFC understood that its role was not to kill the pharmaceutical pipeline with “logic” like that shown by Judges Lourie and Chen in this case. That time is, apparently long gone. Goes hand-in-hand with the silencing of Judge Newman. Judge Rich must be turning over in his grave.
+1
Invalidation rabbits-in-a-hat.
Everyone enjoys a little magic, right?
+1
Seems like an easy playbook going forward:
1) applications filed before the clinical trials are invalid under 112 written description and/or enablement; and
2) applications filed after the clinical trials are invalid under 102/103.
point 1 is contrary to law. Patentability of an invention, and approval to use on humans per the FDA, are distinct inquiries.
Point 2 is right: don’t wait to file.
Unless of course, the claim bridges that gap.
After all, if you invented a substance to be used on humans then it is not an either/or situation, but is a both situation.
As to Point 2, possession is required at the time of filing.
Given the number of (claimed) drugs that
F
A
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(and thus do not possess), your words appear to come across as advising to file prematurely.
“Patentability of an invention, and approval to use on humans per the FDA, are distinct inquiries.”
Why should they be? Utility, enablement, and obviousness are all dependent on a POSA’s views–paramount among them is the POSA’s view of whether the drug will actually work or not. I see no reason the law should force us to ignore the most important consideration of pharmaceutical innovation.
Nobody is “ignoring” the fact that both the PTO and FDA require that the administered drug has a useful effect. The issue is that FDA approval requires additional showings that are not required for a patent.
That very much depends on the claims.
As has been noted.
In 101/112 cases at least it seems like the PTO defines “has a useful effect” as “it’s not inconceivable that it may have some useful effect”, and permits extremely early stage testing that is basically useless to suffice for a showing.
Utility is notoriously an extremely low legal bar to clear.
As it was intended to be (before the Supremes got involved).
… and of course, the utility bar IS tied to the scope of the claims.
Pharma wants claims that cover use in humans – they need to possess that at the time of filing.
As was ever the case (as written by Congress).
What is sufficient to render claims invalid may not be sufficient to render them enabled. That dichotomy is the issue.
I am old enough to remember a time the USPTO essentially required positive clinical trial results to show utility for method of treatment claims. That is no longer the case for utility, but can be for showing enablement.
” Prior to the Proposed Utility Guidelines that were published on January 3, 1995, the standards for utility and operability in Group 1800 did not correspond with the patent law, its own internal rules, and the constitutional mandate to promote the useful arts. The PTO was under a misconception that relaxing its utility and enablement standards for
human therapeutic inventions placed the public at risk. A patent, however, does not guarantee that the disclosed invention will ever be practiced. The FDA must approve any human therapeutic composition before it can be advertised, used, or sold to the U.S. public. Therefore, unlike other technology areas, e.g., the mechanical or electrical arts, in
the biotechnology and pharmaceutical field, there is a second layer of *252 government standing between the U.S. public and the patented invention.
According to the MPEP, examiners should follow two principles when evaluating the sufficiency of the disclosure of utility in “drug” cases:
(1) The same basic principles of patent law which apply in the field of chemical arts shall be applicable to drugs, and
(2) the PTO shall confine its examination of disclosure of utility to the application of patent law principles, recognizing that other agencies of the government have been assigned the responsibility of assuring conformance to the standards established by statute for the advertisement, use, sale, or distribution of drugs. [n.206]”
link to ipmall.info
+1
that pretty much sums it up for me, glad I’m retiring!