Thursday, November 30, 2017

The MS drug ALKS 8700

There has been some recent buzz in the multiple sclerosis community over ALKS 8700 :

ALKS 8700 is currently in Phase 3 development for MS. Alkermes plans to seek approval of ALKS 8700 under the 505(b)(2) regulatory pathway referencing Biogen’s TECFIDERA® (dimethyl fumarate). The registration package for ALKS 8700 will include pharmacokinetic bridging studies that establish bioequivalence to TECFIDERA and data from a two-year safety study known as EVOLVE-MS-1. Initial safety data from EVOLVE-MS-1 were recently presented at MSParis2017, the 7th Joint Meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) in October


The compound is related to Tecfidera:

ALKS 8700 is a monomethyl fumarate (MMF) molecule that the company believes can perform better than dimethyl fumarate (Tecfidera, marketed by Biogen), a U.S. Food and Drug Administration-approved oral therapy for relapsing forms of MS.


A Phase 3 clinical trial, called EVOLVE MS (NCT02634307), is now evaluating the long-term safety and tolerability of ALKS 8700 in an estimated 800 people with relapsing MS. The study, which is recruiting patients at more than 100 sites across the U.S. and Europe, will measure safety via adverse events recorded over its 96 weeks. It is expected to end in December 2020.

The EVOLVE-MS clinical development program also includes an elective head-to-head study comparing the gastrointestinal tolerability of ALKS 8700, at 462 mg twice daily, and Tecfidera at 240 mg twice daily. This is a five-week study involving some 420 people with relapsing MS. Common gastrointestinal symptoms, including nausea, vomiting, upper and lower abdominal pain and diarrhea, will be evaluated using two patient-reported symptom rating scales: the Individual Gastrointestinal Symptom and Impact Scale (IGISIS) and the Global Gastrointestinal Symptom and Impact Scale (GGISIS).


From US 9505776 (first inventor Zeidan; Prior Publication 20140275048, September 18, 2014 ):

[0005]Fumaderm®, an enteric coated tablet containing a salt mixture of monoethyl fumarate and dimethyl fumarate (DMF) which is rapidly hydrolyzed to monomethyl fumarate, regarded as the main bioactive metabolite, was approved in Germany in 1994 for the treatment of psoriasis. Fumaderm® is dosed TID with 1-2 grams/day administered for the treatment of psoriasis. Fumaderm® exhibits a high degree of interpatient variability with respect to drug absorption and food strongly reduces bioavailability. Absorption is thought to occur in the small intestine with peak levels achieved 5-6 hours after oral administration. Significant side effects occur in 70-90% of patients (Brewer and Rogers, Clin Expt'l Dermatology 2007, 32, 246-49; and Hoefnagel et al., Br J Dermatology 2003, 149, 363-369). Side effects of current FAE therapy include gastrointestinal upset including nausea, vomiting, diarrhea and/or transient flushing of the skin.


[0015]Because of the disadvantages of dimethyl fumarate described above, there continues to be a need to decrease the dosing frequency, reduce side-effects and/or improve the physicochemical properties associated with DMF. There remains, therefore, a real need in the treatment of neurological diseases, such as MS, for a product which retains the pharmacological advantages of DMF but overcomes its flaws in formulation and/or adverse effects upon administration. The present invention addresses these needs.

The first claim is to a compound:

A compound of Formula (Ia), or a pharmaceutically acceptable salt thereof: (...)

On page 12 of the Office Action of October 2015, the examiner notes the specification discloses that the claimed compounds are prodrugs of monomethyl fumarate. Citing Genentech, 108 F.3d at 1366, at page 15 of the OA, the examiner initially rejected the claims on written description and enablement grounds.
Following amendment and argument, the claims were allowed, all with the understanding that the claimed compounds were prodrugs of monomethyl fumarate.

**As to possible patent issues:

If the generic company's application implicates a brand-name drug covered by a patent, the generic company must also certify in its 505(b)(2) application or ANDA that "such patent is invalid or will not be infringed by the manufacture, use, or sale of the new drug for which the application is submitted." Id. §§ 355(b)(2)(A)(iv); (j)(2)(A)(vii)(IV). This is known as a "Paragraph IV certification."

from FTC v. Abbvie, 107 F. Supp. 3d 428

In addition to the obligation to reference the drug upon which the 505(b)(2) application relies and certify to its patents, a 505(b)(2) applicant must also provide notice of any Paragraph IV certification to owner of the RLD and each patent owner, explaining the factual and legal basis for the applicant's opinion that the patent is invalid or not infringed. See 21 U.S.C. § 355(b)(3)(C)-(D). This notice enables the owners of the RLD and its related patents to litigate the patent issue before FDA approves the 505(b)(2) NDA applicant's new drug product.7 To this end, upon the filing of a Paragraph IV certification, FDA is required to stay any approval for at least 45 days, and up to 30 months, in order to permit any potential patent litigation to proceed. See 21 U.S.C. § 355(c)(3)(C), (j)(5)(B)(iii).

from Takeda, 78 F. Supp. 3d 65 (D DC 2015)


Rather than conducting its own clinical studies, Reliant depended on the data of another, already approved, fenofibrate drug called TriCor®, which was developed by a French company named Laboratories Fournier ("Fournier") and distributed by Abbott in the United States.5 Antara received FDA approval in November 2004, and Reliant began marketing the drug in February 2005. Reliant chose not to make a certification under § 505(b)(2)(A)(iv) that Antara did not infringe any patents in the Orange Book or that those patents were invalid, but elected to market Antara immediately [*228] after gaining FDA approval.6 That marketing exposed Reliant to a possible infringement suit from Abbott, making Reliant's launch of Antara "at risk."7 In a prophylactic maneuver, Reliant filed a declaratory judgment action in the United States District Court for the District of Delaware in June 2004, seeking a declaration of non-infringement with respect to four of Abbott's [**9] fenofibrate patents, U.S. Patent Nos. 6,074,670 (the "'670 patent"), 6,277,405 (the "'405 patent"), 6,589,552 (the "'552 patent"), and 6,652,881 (the "'881 patent"). Reliant also argued that the patents were unenforceable due to inequitable conduct. Abbott counterclaimed for infringement of two of the four patents. Despite that lawsuit, Antara's net sales in 2005 were $23.5 million, and for the first half of 2006 they were $18.9 million.

from Ethypharm, 707 F.3d 223 (CA3 )

***Of prodrug cases:

From 2016 U.S. Dist. LEXIS 8757

In its initial formulation, tenofovir needed to be injected intravenously. In 1997, defendant Gilead Sciences, Inc., obtained a patent on a "prodrug" of tenofovir, which could be administered orally and converted into its active ingredient once metabolized in the human body. That prodrug was called tenofovir disoproxil fumarate ("TDF").


TDF had side effects involving bone and kidney toxicity. In 2002, Gilead hired physicians to conduct safety and efficacy research into an alternative formulation of a tenofovir prodrug, called tenofovir alafenamide fumarate ("TAF"). Meanwhile, in 2004, Gilead publicly announced that it had abandoned development of TAF, although it filed seven patent applications relating to the use of TAF between 2004 and 2005. Gilead then resumed its clinical trials in 2011. In 2014, it published a study concluding that TAF had a higher absorption rate than TDF, thereby reducing the bone and kidney toxicity side effects.

From 2015 U.S. Dist. LEXIS 110099

The Adams patent discloses and claims the use of "prodrugs." Tr. 876-77. A "prodrug"—like the claimed mannitol ester of bortezomib—is a drug compound "that . . . upon administration rapidly releases the active agent." [*15] Tr. 256 (Repta); see also Tr. 256 (Repta); Tr. 766 (Anderson).

See Amy Kapczynski et al., Polymorphs and Prodrugs and Salts (Oh My!): An Empirical Analysis of "Secondary" Pharmaceutical Patents, 7 PLoS One e49470 (2012)


Andrew W. Torrance, Physiological Steps Doctrine, 23 Berkeley Tech. L.J. 1471, 1472-1505 (2008). On nearly a dozen sete occasions federal courts have considered whether human products of "in vivo conversion" (that is, the conversion of a first chemical species into a distinctly different second chemical species by the body's own physiological processes) constitute patentable subject matter that can be protected from infringement by valid and enforceable patent claims. These cases all consider whether human administration of an unpatented "prodrug" (or drug precursor) that is subsequently converted within the human body into a different, therapeutically active, and patented, drug can trigger patent infringement. Although well-settled principles of patent law mandate that infringers are strictly liable for making or using a claimed invention, remarkably no court has finally found infringement for the in vivo production of a patented drug within the human body. Id.

From 45 IDEA 165

There remains one question to ponder when evaluating the amount of evergreen (i.e., improvement) patenting that might be expected in the post-reform Hatch-Waxman universe, namely, the impact that the Schering Corporation v. Geneva Pharmaceuticals n286 decision might have on such practices of innovative pharmaceutical companies. This is a particularly interesting issue to consider in the context of FDA's new listing regulations preventing the listing of patents directed to metabolites, intermediates and packaging. In Schering, the Federal Circuit affirmed the District Court's decision finding that a patent to a prodrug, namely to the drug that is actually administered to a patient, inherently anticipates a patent to the metabolite that is produced from the prodrug in the body. n287 Judge Rader reasoned as follows:
Patent law . . . establishes that a prior art reference which expressly or inherently contains each and every limitation of the claimed subject matter anticipates and invalidates . . . In . . . prior cases, however, inherency was only necessary to supply a single missing limitation that was not expressly disclosed in the prior art. This case, as explained before, asks this court to find anticipation when the entire structure of the claimed subject matter is inherent in the prior art.
Because inherency places subject matter in the public domain as well as an express disclosure, the inherent disclosure of the entire claimed subject matter anticipates as well as inherent disclosure of a single feature of the claimed subject matter. The extent of the inherent disclosure does not limit its anticipatory effect. In general, a limitation or the entire invention is inherent and in the public domain if it is the "natural result flowing from" the explicit disclosure of the prior art.
This court sees no reason to modify the general rule for inherent anticipation in a case where inherency supplies the entire anticipatory [*221] subject matter. n288


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