By Jonathan B. (J.B.) Fitzgerald, Ph.D., J.D., Snell & Wilmer, L.L.P.
Pharmaceutical patents that cover drugs or methods of treatment often contain claims that refer to dosages or dosage ranges. For these dosages and dosage ranges to be valid under the law, they must meet the written description requirement, which means they must be sufficiently described in the disclosure (specification) of the patent.
In Biogen Intl. v. Mylan1 (Biogen), the Federal Circuit invalidated claims in one of Biogen’s patents based on its finding that a claimed dosage limitation was insufficiently described in the disclosure and, thus, failed to meet the written description requirement. Subsequent to this decision, the Federal Circuit denied Biogen’s petition for rehearing of the case.2
The Biogen decision along with the Indivior UK Limited v. Dr. Reddy’s Laboratories S.A.3 (Indivior) decision (previously reported on by our group here) require exacting standards for meeting the written description requirement for claimed ranges and claimed dosages. Understanding these exacting standards is important because pharmaceutical patents that claim dosages or dosage ranges may be susceptible to invalidity challenges under the written description requirement, if these standards are not met.
This paper (i) outlines the Federal Circuit’s holding that Biogen’s claimed dosage failed to meet the written description requirement, (ii) analyzes the impact of unclaimed subject matter in the Indivior and Biogen cases, and (iii) reviews the Federal Circuit’s analysis of the data in Biogen’s patent. This paper concludes with (iv) the key takeaways of the written description standard for dosages and dosage ranges after the Indivior and Biogen cases.
i. Biogen’s Claimed Dosage Failed To Meet The Written Description Requirement
Biogen sued Mylan in response to Mylan’s attempt to get regulatory approval of a drug that was the generic equivalent of Biogen’s Tecfidera (dimethyl fumarate, DMF), a multiple sclerosis drug. Biogen initially asserted a number of patents in litigation; on appeal, Biogen’s U.S. Patent No. 8,399,514 remained in suit. The ‘514 patent claimed methods of treating multiple sclerosis (MS). Portions of claim 1, which is representative, are provided below:
1. A method of treating a subject in need of treatment for multiple sclerosis comprising orally administering…a therapeutically effective amount of dimethyl fumarate, monomethyl fumarate, or a combination thereof…wherein the therapeutically effective amount of dimethyl fumarate, monomethyl fumarate, or a combination thereof is about 480 mg per day. (Italics added)
At issue in the Biogen case was whether the dosage limitation of “about 480 mg per day” had sufficient support in the specification to meet the written description requirement. The hallmark of the written description requirement is showing possession.4 The Federal Circuit concluded that the specification failed to meet this possession standard for the dosage limitation despite the following relevant disclosures in the specification.
Related to treating MS, the specification stated, “Provided are certain compounds treating neurological diseases…, such as, e.g., multiple sclerosis.” With respect to a dosage of DMF, the specification stated, “For example, an effective dose of DMF…to be administered to a subject orally can be…from about 480 mg to about 720 mg per day.” Moreover, the specification disclosed data showing that in vivo treatment with DMF resulted in modulation of a transcription factor that would be expected to carry out the therapeutic effect of treating MS. Thus, seemingly consistent with the elements of claim 1, the specification disclosed a method of treating MS using DMF at a dosage of 480 mg per day, and the specification provided experimental evidence that such a treatment was effective.
To support its finding that these disclosures were insufficient to show possession of the dosage limitation, the Federal Circuit pointed to, amongst others, (i) the disclosure of neurological disorders other than MS and the disclosure of dosages and ranges that were not claimed, and (ii) the alleged failure of the specification to show therapeutic efficacy of the claimed dosage
With regard to unclaimed disclosures of dosages and ranges, the Federal Circuit pointed out that the specification listed approximately three dozen neurological disorders in addition to MS. Also, the court stressed that the specification referred to numerous dosage ranges. Further, the court emphasized that the claimed dosage of 480 mg per day was listed only once at the end of one of the dosage ranges and as part of a series of dosage ranges.
With regard to the alleged failure of the inventors to show therapeutic efficacy, the Federal Circuit began with the proposition that the case turns on whether the “specification describes ‘possession’ of the claimed therapeutically effective DMF480-dose limitation to treat MS.” The court concluded that the specification failed in this task. As evidence of this failure, the court referenced the testimony of one of the inventors who stated that it “was never the focus of [his] work to inform the clinical dosing of [DMF].” Additionally, the court pointed to the fact that the claimed dose of 480 mg per day was not listed independently, but rather was only listed as part of a dosage range, amongst numerous dosage ranges.
ii. The Federal Circuit’s Analysis Of Unclaimed Subject Matter In Biogen And Indivior
A long-standing principle of the written description requirement is that the specification does not need to provide verbatim support to meet the written description requirement.5 As we reported in our article on the Indivior case, the Federal Circuit seemingly departed from this standard in finding that a claimed range that was disclosed in tables in the specification did not meet the written description requirement because its end values were not expressly recited in the specification.
In its evaluation of the dosage limitation in the Biogen case, the Federal Circuit seemingly took an even more stringent standard for meeting the written description requirement than it did in the Indivior case. Unlike the range in Indivior, the dosage limitation of DMF of “about 480 mg per day” was explicitly set forth in the specification. Thus, whereas in Indivior the Federal Circuit invalidated a claimed range because its end values were not explicitly set forth in the specification, in Biogen, the Federal Circuit invalidated a dosage limitation despite its value being explicitly set forth as an end value of a range in the specification.
To support its findings in both the Indivior and Biogen cases that claimed ranges and the dosage limitation, respectively, failed to meet the written description requirement, the Federal Circuit cited unclaimed disclosures. In Indivior, the Federal Circuit referred to the unclaimed disclosures suggesting that the claimed polymer could function outside of any range and to the unclaimed disclosures that referred to values that fell significantly outside of the claimed range. In Biogen, the Federal Circuit referred to the unclaimed disclosures related to the numerous neurological disorders other than MS, and to the series of unclaimed dosage ranges that were referenced in the specification. In both the Indivior and Biogen cases, the court cited these unclaimed disclosures as evidence that the inventors failed to possess the claimed range or the claimed dosage.
The dissent in the denial of the petition for rehearing of the Biogen case argued that the majority’s emphasis on unclaimed disclosures was an error. According to the dissent, the unclaimed disclosures were irrelevant because the singular disclosure of the claimed dosage was sufficient to meet the written description requirement. Further, according to the dissent, the majority’s opinion suggested the absurd result in which the disclosures of claimed subject matter would be arbitrarily compared to those of the unclaimed subject matter to determine whether the claimed subject matter is properly supported.
iii. The Federal Circuit’s Analysis Of The Experimental Data In Biogen
In Biogen, the Federal Circuit concluded that the specification did not provide sufficient support for a therapeutic dose of DMF to treat MS. The court drew this conclusion despite the specification reporting in vivo data showing that DMF treatment modulates levels of a transcription factor, which is responsible for protecting cells from neurodegeneration that is often associated with MS. Moreover, the dosage of DMF used to modulate the transcription factor (5 to 15 mg/kg, twice per day) was roughly in line with providing a 480 mg per day dose of DMF (the claimed dosage) to a human subject (depending on the weight of the human subject). These disclosures arguably suggest that the specification did provide support for a therapeutic dose, by experimentally showing that the drug was able to mechanistically modulate a factor that would be expected to carry out the therapeutic effect of treating MS.
It is unclear precisely what experimental evidence would have satisfied the Federal Circuit, but it seems that the court was requiring a showing that the claimed dose was clinically effective. The court seemed receptive to Mylan’s argument that the claims failed to meet the written description requirement because the disclosure lacked Phase 3 clinical data (referring to the human, clinical trial in which DMF was tested in humans). Indeed, the majority opinion referenced the disclosure’s having been filed before the Phase 3 clinical study commenced, and the majority relied on the inventor’s testimony that his work’s focus was unrelated to identifying a clinical dose of DMF.
Biogen argued that clinical efficacy data was not necessary to meet the written description requirement, rather only therapeutic efficacy was necessary, and Biogen argued that the data in the disclosure showed evidence of therapeutic efficacy. Consistent with Biogen’s position, the dissent alleged that the majority opinion improperly conflated therapeutic efficacy with clinical efficacy. This, according to the dissent, caused the majority to erroneously require clinical data to satisfy the written description requirement. The dissent in the denial for the petition for rehearing went even further, suggesting that in requiring a showing of human efficacy, the majority had moved into the province of the FDA.
iv. Takeaways For Industry After Indivior and Biogen
The Biogen and Indivior cases contain exacting standards for meeting the written description requirement, for claimed dosages and dosage ranges. In both cases, disclosures of unclaimed dosages and dosage ranges weighed against a finding that the claimed dosage and dosage range met the written description requirement. Moreover, the Biogen case seemingly provided a significantly heightened (and ambiguous) standard as to what is necessary to provide sufficient written support that a claimed dose is therapeutically effective. The Federal Circuit seemed to indicate that clinical/human data was required to show adequate written support of a therapeutic effect.
It is unclear whether the standard on unclaimed subject matter and a presumptively higher bar for showing therapeutic efficacy will continue as trends in future Federal Circuit cases that examine whether dosages and dosage ranges have sufficient written support. What is clear is that the Indivior and Biogen cases have now set precedents that can be used in future cases. Thus, it is possible that pharmaceutical patent claims that include dosages and/or dosage ranges may now be more susceptible to invalidity challenges under the written description requirement, particularly if the specification discloses too many unclaimed dosages and/or dosage ranges or if the specification fails to meet the Biogen’s presumptively heightened standard for showing therapeutic efficacy.
- 18 F.4th 1333 (2021).
- Biogen Intl. GMBH, Biogen MA, Inc., v Mylan Pharmaceuticals Inc., 28 F.4th 1194 (2022).
- 18 F. 4th 1323 (2021).
- Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (2010) (en banc).
- See, in re Lukach, 442 F.2d 967 (C.C.P.A. 1971); and See, In re Wertheim, 541 F.23d 257 (C.C.P.A. 1976).
About The Author:
Jonathan B. (J.B.) Fitzgerald, Ph.D., is an associate at Snell & Wilmer. He is a registered patent attorney and has a Ph.D. in molecular physiology. His primary practice area involves preparing and prosecuting patent applications in the biotechnology and the life sciences