Innovator companies in the biopharmaceutical space are looking to their patent counsel for creative patent claiming strategies to protect their assets. In this article, using the Federal Circuit opinions in Teva Pharms. v. Corcept Therapeutics, Vanda v. West-Ward, and Sanofi v. Watson as a foundation, we describe a strategy of enhancing chances of success against generic or biosimilar challengers by claiming clinical trial protocols and results, and other information that appears on a drug product label, i.e., by claiming what was approved by the FDA. The article will also explore creative claim strategies that take advantage of 35 U.S.C. 112(f)'s means-plus-function terminology. These strategies could help create strong US patents and provide additional protections for biopharmaceutical innovations.
I. CLAIM STRATEGY BASED ON CLAIMING CLINICAL TRIAL RESULTS
The opinion in Sanofi v. Watson, 875 F.3d 636 (Fed. Cir. 2017), showcases intriguing possibilities for patent owners in the biopharma industry whose patent counsel works closely with clinical trial teams and files US patent applications that include and claim innovations arising from clinical trial results.
Under the rationale of Sanofi v. Watson, when a generic or biosimilar manufacturer copies a label to obtain FDA approval, an innovator biopharma company may successfully assert induced infringement of method-of-treatment claims that facially seem very narrow, but closely correspond with what the FDA approved and is included in the label, including the clinical trial results set forth in the label.
For this strategy to work in the US, of course, the patent application must be drafted to include details of the clinical trial information and results and must be filed before any published clinical trial information or results become disabling prior art, as set out under 35 U.S.C. § 102(a)(1), in the absence of any 35 U.S.C. § 102(b)(1) exceptions.
Patent teams should therefore coordinate and communicate early and frequently with the clinical trial teams and regulatory teams of the new drug application (NDA) or biologics license application (BLA) holder/reference product sponsors to help facilitate this strategy.
Practitioners should consider including in the patent specification and claims the specific information that cannot be carved out by the generic or biosimilar manufacturer, such as key safety signals, dosage adjustments in methods of treatment, and references to the clinical studies section in the Indication and Usage section of the label.
A. Details of Sanofi v. Watson Opinion
The invention at issue in Sanofi v. Watson, supra, was a method of treating heart rhythm problems in patients with atrial fibrillation by administering dronedarone, an antiarrhythmic agent, which is marketed under the brand name Multaq®.
Sanofi filed a patent application on its dronedarone composition in 1998. After approximately a decade of clinical trials and successful Phase III results, Sanofi obtained FDA approval of Multaq®.
Sanofi later obtained US Patent No. 8,410,167 ("the '167 patent"), which disclosed the Phase III clinical trial results, including details of contraindicated symptoms, severe heart failure dangers, and patient cardiovascular risk factors. Claim one of the '167 patent recited those same details:
A method of decreasing a risk of cardiovascular hospitalization in a patient, said method comprising administering to said patient an effective amount of dronedarone or a pharmaceutically acceptable salt thereof, twice a day with a morning and an evening meal, wherein said patient does not have severe heart failure, (i) wherein severe heart failure is indicated by: a) NYHA Class IV heart failure or b) hospitalization for heart failure within the last month; and (ii) wherein said patient has a history of, or current, paroxysmal or persistent non-permanent atrial fibrillation or flutter ; and (iii) wherein the patient has at least one cardiovascular risk factor selected from the group consisting of:
- an age greater than or equal to 75;
- hypertension ;
- a history of cerebral stroke or of systemic embolism ;
- a left atrial diameter greater than or equal to 50 mm; and
- a left ventricular ejection fraction less than 40%.
The Clinical Studies section of the Multaq® label similarly included all of those details. The label also referred to the Clinical Studies section in the label's Indications and Usage section. The label reads: "Multaq is indicated to reduce the risk of hospitalisation for atrial fibrillation in patients in sinus rhythm with a history of paroxysmal or persistent atrial fibrillation [see Clinical Studies (14)]." Id. at 642-643.
The Federal Circuit affirmed the district court holding that Sanofi's patent was valid and that the generic label provided sufficient basis for a finding of intentional encouragement of infringement, and thus inducement to infringe. Id. at 646.
[T]he inference in the present case is based on interpreting the label's express statement of indications of use and the internally referred-to elaboration of those indications.
Because of the reference to the Clinical Studies section (14) within the Indications and Usage section of the label, "the label thus directs medical providers to information identifying the desired benefit for only patients with the patent-claimed risk factors." Id. at 645.
Using this label/patent application combination strategy, Sanofi successfully protected the innovation arising out of the Phase III clinical trial results and achieved additional scope of patent protection, with 10 more years of patent exclusivity compared to the dronedarone composition patent.
B. Vanda v. West-Ward
In the 2018 Federal Circuit decision in Vanda Pharmaceuticals v. West-Ward Pharmaceuticals, Vanda was also rewarded with a finding of induced infringement of its US Patent No. 8,586,610 ("the '610 patent") because of the use of a similar label/patent application claiming clinical trial results.
Claim 1 (claiming the clinical trial results set forth in the label for FANAPT®):
A method for treating a patient with iloperidone, wherein the patient is suffering from schizophrenia, the method comprising the steps of:
determining whether the patient is a CYP2D6 poor metabolizer by: obtaining or having obtained a biological sample from the patient; and
performing or having performed a genotyping assay on the biological sample to determine if the patient has a CYP2D6 poor metabolizer genotype; and
if the patient has a CYP2D6 poor metabolizer genotype, then internally administering iloperidone to the patient in an amount of 12 mg/day or less, and if the patient does not have a CYP2D6 poor metabolizer genotype, then internally administering iloperidone to the patient in an amount that is greater than 12 mg/day, up to 24 mg/day,
wherein a risk of QTc prolongation for a patient having a CYP2D6 poor metabolizer genotype is lower following the internal administration of 12 mg/day or less than it would be if the iloperidone were administered in an amount of greater than 12 mg/day, up to 24 mg/ day.
Safety/efficacy features of the drug led to claims of "a specific method of treatment for specific patients using a specific compound at specific doses to achieve a specific outcome." Vanda Pharms. Inc. v. West-Ward Pharms. Int'l Ltd., 887 F.3d 1117, 1136 (Fed. Cir. 2018).
The Abbreviated New Drug Application (ANDA) filer, West-Ward, submitted a proposed label that was found to be "substantially identical" to Vanda's label. Id. at 1122.
The Federal Circuit rejected West-Ward's argument that Vanda should present evidence of actual past direct infringement. It stated that "the contents of the label itself may permit inference of specific intent to encourage, recommend, or promote infringement". Id. at 1129.
The district court made factual findings that the proposed label 'recommends' that physicians perform the claimed steps ... and its analysis of the proposed label to assess potential direct infringement by physicians was proper under our precedent.
Id. at 1130.
The Federal Circuit affirmed the district court's finding that the label showed specific intent to encourage infringement by doctors.
Like Sanofi, Vanda successfully protected its innovative iloperidone dosing regimen based on CYP2D6 genotype and achieved an additional decade of patent exclusivity for the claimed method of treatment compared to the compound patent.
C. Claiming the Unexpected Results
In Teva Pharms. USA, Inc. v. Corcept Therapeutics, Inc., 18 F.4th 1377 (Fed. Cir. 2021), the Federal Circuit affirmed the Final Written Decision of the Patent Trial and Appeal Board ("the Board") holding Teva failed to show all the challenged claims in PGR2019-00048 would have been obvious.
Corcept markets a 300 mg mifepristone tablet under the name Korlym®. In approving Corcept's NDA for Korlym®, the U.S. Food and Drug Administration ("FDA") required Corcept to conduct a drug-drug interaction clinical trial of mifepristone and ketoconazole (a strong CYP3A4 inhibitor). Id. at 1379. The FDA also provided an Office of Clinical Pharmacology memorandum ("Lee") explaining that the drug-drug interaction study was necessary to determine whether there was a safety risk in co-administration of CYP3A inhibitors and mifepristone. Id.
Corcept's original Korlym® label recommended a starting dose of 300 mg once daily up to a maximum of 1200 mg once daily, but with a warning to limit the mifepristone dose to 300 mg once daily when used with strong CYP3A inhibitors. Id.
Based on the subsequent drug-drug interaction study, Corcept applied for and received U.S. Patent No. 10,195,214 ("the '214 patent"). Claim 1 of the '214 patent read:
1. A method of treating Cushing's syndrome in a patient who is taking an original once-daily dose of 1200 mg or 900 mg per day of mifepristone, comprising the steps of:
reducing the original once-daily dose to an adjusted once-daily dose of 600 mg mifepristone,
administering the adjusted once-daily dose of 600 mg mifepristone and a strong CYP3A inhibitor to the patient,
wherein said strong CYP3A inhibitor is selected from the group consisting of [ ].
The '214 patent reflects the drug-drug interaction study by allowing up to 600 mg of mifepristone in combination with the strong inhibitor. The original label clearly contradicts that.
Corcept sued Teva for infringement of the '214 patent, and Teva then sought post-grant review of claims 1-13. Teva argued the '214 claims were obvious based on the Korlym® label and Lee, optionally in combination with FDA guidance on drug-drug interaction studies. Id. at 1380.
The Board rejected Teva's obviousness argument, finding that Teva failed to show that a person of ordinary skill in the art ("POSITA") "would have had a reasonable expectation of success for safe co-administration of more than 300 mg of mifepristone with a strong CYP3A inhibitor." Id. This conclusion followed from the Board's construction of the claims to require safe administration of mifepristone (even though that was not recited in the claims) and the Board's rejection of Teva's expert's testimony that "based on the Korlym® label and Lee, 'it was reasonably likely that 600 mg [per day of mifepristone] would be well tolerated and therapeutically effective when co-administered with a strong CYP3A inhibitor.'" Id. at 1381. The Board found that testimony inconsistent with Teva's expert's later testimony that a POSITA "would have no expectation as to whether the co-administration of 600 mg of mifepristone with ketoconazole would be safe." Id. at 1381-82. (emphasis in original).
The Federal Circuit affirmed the Board's decision. Although Teva argued that the Board erred in its reasonable expectation of success analysis by requiring precise predictability of a specific dosage, the Federal Circuit disagreed. "The Board applied the correct standard, requiring only a reasonable expectation of success and tying its analysis to the scope of the claimed invention." Id. at 1382. Acknowledging that "[a]bsolute predictability is not required[,]" the court placed the burden on Teva to prove a reasonable expectation of success for a 600 mg dosage. Id. at 1381.
But Teva did not establish "that [a skilled artisan] would reasonably have expected co-administration of more than 300 mg of mifepristone with a strong CYP3A inhibitor to be safe for the treatment of Cushing's syndrome or related symptoms in patients." Id. The evidence showed that a POSITA would have had "no expectation as to whether co-administering dosages of mifepristone above the 300 mg/day threshold set forth in the Korlym label would be successful.'" Id. (emphasis in opinion). "Because there was no expectation of success for any dosages over 300 mg per day, there was no expectation of success for the specific 600 mg per day dosage. ... Nothing about this analysis required precise predictability, only a reasonable expectation of success tied to the claimed invention." Id. Monotherapy doses above 300 mg per day do not change this conclusion since the claim is limited to co-administration doses. Id. at 1383. The Federal Circuit upheld the Board's finding that a POSITA would not have expected monotherapy and co-administration dosages to behave similarly. Id.
The Court concluded that substantial evidence supported the Board's finding that the condition ranges disclosed in the prior art did not overlap with the claimed invention. Id. at 1383. As noted above, the prior art warned against co-administration with doses of more than 300 mg per day when used with strong CYP3A inhibitors. Id. at 1382-1383.
Showing obviousness requires both a motivation to modify/combine the prior art AND a reasonable expectation of success in arriving at the claimed invention. Beyond looking to the prior art to determine if it suggests doing what the inventor has done, this case reinforces that one must also consider if the art provides the required expectation of succeeding in that endeavor. "Obviousness does not require absolute predictability, but a reasonable expectation of success is necessary." In re Clinton, 527 F.2d 1226, 1228 (CCPA 1976).
This case also highlights the importance of claim construction. Corcept's claims were construed to require safe administration of mifepristone, even though that was not explicitly recited in the claims. But the Board and the Federal Circuit focused on the clinical trial results, which Corcept had claimed. Claim construction was an important underpinning of the conclusion that the success of the claimed invention could not have been reasonably expected.
D. Why Draft a Very Narrow Claim?
Generic or biosimilar manufacturers generally need to propose the same or highly similar labeling and could be captured on the basis of inducement to infringe. The generic label, by directing doctors and patients on the use of the drug product, intentionally encourages infringement (induces infringement) of the branded drug maker's patent claims. Claims directed to innovations based on clinical trial results that are fully described in the specification are more likely to be supported under the written description and enablement requirements. Successful execution of this strategy requires close communication with the client, careful timing and control over public disclosures, and the ability to appropriately draft a patent specification to include the requisite elements.
Originally published by International In-House Counsel Journal.
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