Formulation and Administration Claims Asserted in Hatch-Waxman

In Cephalon, Inc. v. Slayback Pharma Ltd. Liab. Co., the Federal Circuit summarily affirmed beneath Rule 36 the district courtroom’s resolution that each one asserted claims of the asserted patents usually are not invalid, and that Defendants infringed and induced infringement. Cephalon, Inc. v. Slayback Pharma Ltd. Liab. Co., 456 F. Supp. 3d 594 (D. Del. April 27, 2020), aff’d, 856 Fed. App’x. 309 (Fed. Cir. Aug. 13, 2021), reh’g denied (Fed. Cir. Oct. 15, 2021).^[1]

Background

Teva Prescription drugs Int’l GmbH, Cephalon, and Eagle Prescription drugs sued Apotex, Fresenius Kabi USA, Mylan Labs., and Slayback Pharma beneath the Hatch-Waxman Act, 35 U.S.C. § 271(e)(2)(A). Defendants had filed Abbreviated New Drug Purposes (“ANDAs”) to market generic variations of Bendeka®. Bendeka®‘s energetic ingredient is bendamustine hydrochloride (referred to by the events as bendamustine). The patents at subject had been U.S. Patent Nos. 9,265,831 (“the ’831 patent”), 9,572,797 (“the ‘797 patent”), 9,144,568 (“the ‘568 patent”), 9,597,399 (“the ‘399 patent”), and 9,572,887 (“the ’887 patent”).

Defendants unsuccessfully argued that the asserted claims had been invalid for obviousness, indefiniteness, lack of enablement, and lack of written description.

District Court docket Choice

Formulation Claims Not Proven to Have Been Apparent

The asserted formulation claims (claims 2, 3, and 5 of the ’831 patent; claims 9 and 11 of the ’797 patent) train a non-aqueous liquid composition that accommodates:

1. bendamustine (or a pharmaceutically acceptable salt thereof);

2. about 5% to about 10% by quantity of the solvent propylene glycol (PG);

3. the solvent polyethylene glycol (PEG);

4. one of many following ratios of PEG to PG: about 95:5, about 90:10, about 85:15, about 80:20, and about 75:25; and

5. a stabilizing quantity of an antioxidant.

Two claims additionally specify elements and portions: (1) declare 11 of the ’797 patent requires that “the antioxidant is thioglycerol or monothioglycerol,”^[2]and (2) declare 5 of the ‘831 patent requires that “the bendamustine focus is from about 25 mg/mL to about 50 mg/mL.” Sure claims of the ‘831 and ’797 patents additionally recite stability limitations similar to “lower than or equal to 0.11% PG esters at about 1 month of storage at about 5°C.”

Though the district courtroom agreed that “a POSITA would have had motive to attempt to develop a non-aqueous liquid bendamustine formulation,” the district courtroom was not persuaded that “a POSITA would have utilized in that formulation the PEG and PG solvents, PEG:PG ratios, antioxidant, concentrations of bendamustine, or PG ester stability limitations recited within the asserted claims.” Id. at 605−06. In reality, the courtroom discovered that one reference, Drager “taught away from utilizing protic solvents, similar to PEG and PG, with bendamustine.” Id. at 607. Whereas Defendants argued that “Alam’s disclosure of blending cyclophosphamide with PEG and PG would have motivated a POSITA to make use of these solvents with bendamustine,” the courtroom additionally discovered that Alam wouldn’t have been thought-about as a result of it “involved a compound that degrades otherwise than bendamustine when mixed with PEG and PG.” Id. at 608. As well as, the references didn’t make the recited PEG:PG ratios apparent, and “the liquid bendamustine examples in Defendants’ prior artwork references don’t embrace antioxidants” as required by the claims. Id. at 609. The focus and stability limitations had been equally not proven to be apparent by the asserted references. Id. at 609−11. The inherency argument failed with respect to the steadiness limitation as a result of the property couldn’t be inherently apparent when the mix itself was not proven to be apparent. Id. at 611.

Administration Claims Not Proven to Have Been Apparent

The asserted administration claims (claims 11, 18, and 22 of the ’568 patent; declare 13 of the ’887 patent) recite strategies of treating CLL or NHL⁶with a liquid bendamustine composition. ^[3]Sure claims require administering the bendamustine composition on days one and two of a 21-day cycle for NHL or on days one and two of a 28-day cycle for CLL. One declare requires a bendamustine dose of “about 25 mg/m²to about 120 mg/m².” The asserted administration claims additionally specify administration instances, the longest time being “about quarter-hour or much less,” and administration volumes which might be all 100 mL or much less. Lastly, sure claims specify post-dilution bendamustine concentrations starting from 0.05 mg/mL to 12.5 mg/mL.

The district courtroom concluded that “Defendants didn’t set up by clear and convincing proof {that a} POSITA would have been motivated to mix the prior artwork references to reach on the claimed administrations with an affordable expectation of success.” Id. at 614. Though the district courtroom discovered that the “prior artwork would have motivated a POSITA to succeed in the claimed formulation, dose, and dosing schedule,” different limitations weren’t proven to be apparent. Id.

“It’s undisputed {that a} POSITA would have wished to make use of a steady and ready-to-use formulation as a part of an improved administration technique[,]” however Defendants didn’t show {that a} POSITA would have been motivated to make use of the asserted prior artwork to attain shorter administration instances, decrease volumes, and better concentrations. Id. at 614−19. Defendants’ argued that Eagle’s dialogue of one of many prior artwork references in submissions to the FDA would offer the requisite motivation. The district courtroom rejected this argument for the reason that FDA submission was filed after the precedence dates of the claims and risked being “distorted by hind-sight bias.” Id. at 619.

Plaintiffs submitted goal proof of non-obviousness: skepticism, long-felt want, business success, and business reward. However the courtroom didn’t discover it persuasive. Id. at 619−21. Just like the formulation claims, nevertheless, the district courtroom primarily based its nonobviousness conclusion on the failure of Defendants to ascertain by clear and convincing proof {that a} POSITA would have had motive to mix the prior artwork references to reach on the claimed administrations with an affordable expectation of success. Id. at 620.

Formulation Claims Not Proven to Be Indefinite

Defendants argued that “the claims recite a ‘stabilizing quantity’ [of antioxidant] with no steerage, practical or in any other case, on what diploma of stability is required to acquire some unnamed goal.” The district courtroom disagreed, discovering that Defendants’ argument “conflates (1) whether or not a given antioxidant quantity improves bendamustine’s stability with (2) the extent to which that given antioxidant quantity improves stability. Id. at 621−22.

The written description defines a “stabilizing quantity of antioxidant” as an quantity that “enhance[s] or improve[s] the steadiness of the bendamustine within the compositions described herein[.]” Id. at 622. Plaintiffs submitted knowledgeable testimony that “a POSITA would perceive {that a} stabilizing quantity of an antioxidant consists of any quantity that decreases the quantity of bendamustine degradation after any time interval and at any temperature.” Id. at 622−23. The specification supplies a way for measuring stability and likewise lists “appropriate antioxidant quantities” and “antioxidants,” and supplies examples of “stabilizing” quantities. Id. at 623.

Formulation Claims Not Proven to Lack Enablement

Defendants argued that the asserted formulation claims had been invalid for lack of enablement as a result of there was no disclosure of “the usage of sodium hydroxide (NaOH) or of ‘different undisclosed variables,’”and “a pH adjuster like NaOH is important to acquire the PG ester ranges claimed within the [a]sserted [f]ormulation [c]laims.” Id. However the district courtroom famous that, with out extra, the truth that some claimed formulations didn’t meet all the claimed limitations was inadequate to indicate lack of enablement. Id. Defendants introduced no proof {that a} POSITA must endure undue experimentation to acquire a formulation that met the declare limitations. Id.

Formulation Claims Not Proven to Lack Written Description Help

Defendants argued an asserted declare was invalid for lack of written description primarily based on the identical “absence of any point out of a pH adjuster like NaOH . . . demonstrates that the inventors didn’t have possession of it at the moment.” Id. However the district courtroom didn’t settle for that such absence meant “the asserted formulation patents [to] declare one thing that they don’t describe of their written descriptions.” Id. at 624.

Infringement

Defendants stipulated to infringement of the asserted claims with two exceptions: (1) the ANDA merchandise don’t include the “stabilizing quantity of an antioxidant” required within the formulation claims; and (2) their proposed labeling doesn’t direct physicians to retailer their ANDA merchandise for about 3 months at about 25°C. Id.

The district courtroom discovered that “Defendants’ ANDA merchandise every include 5 mg/mL of the antioxidant monothioglycerol, . . . and the formulation patents’ written description exhibits that 5 mg/mL of monothioglycerol is a stabilizing quantity.” Id. at 625.

With respect to the proposed label, the district courtroom didn’t agree with Defendants’ characterization of the difficulty. The courtroom discovered that “regardless that Defendants’ labeling doesn’t point out storage, Defendants’ ANDA merchandise straight and not directly infringe declare 9 as a result of the PG ester limitation doesn’t require the consumer to retailer the merchandise for 3 months at 25°C. Declare 9′s PG ester limitation describes a attribute of the claimed system; it isn’t a way step and thus, doesn’t require motion to infringe. The declare doesn’t recite testing for the PG ester limitation; it simply describes a composition that will have lower than 0.43% PG esters if one had been to check for them after storing the composition for 3 months at 25°C.” Id. at 625−26. With respect to induced infringement, the courtroom additional discovered that “Defendants will encourage others to manage their ANDA merchandise via their proposed labels. Though Defendants’ proposed labeling doesn’t point out the claimed PG ester limitations, Defendants know ‘that [their ANDA products] meet all the declare limitations and, via [their] proposed label[s], encourage[] sufferers to manage [their ANDA products] in a fashion that infringes the claimed technique.’” Id. at 626.

Take-aways

The burden of creating a prima facie case of obviousness rests with the get together asserting invalidity. This case is a reminder {that a} case could also be selected the grounds {that a} prima facie case will not be established. When responding to a prima facie case, two choices exist: A patent proprietor can both present arguments undercutting a number of of its standards (i.e., “attacking the prima facie case”) or submit proof of nonobviousness (i.e., “rebutting the prima facie case”). In attacking the prima facie case, the practitioner might argue (1) {that a} prior artwork reference can’t be correctly modified or mixed with different references, as a result of, in view of the scope and content material of the prior artwork and the extent of odd ability, the claimed invention was not apparent, and/or (2) that even when modified or mixed as proposed, a POSITA would haven’t any foundation for an affordable expectation of success. 

This case additionally reminds practitioners that knowledgeable testimony as to what a POSITA would perceive could also be useful in opposition to §112 invalidity assertions.

[1] District courtroom order, 2020 U.S. Dist. LEXIS 118941 (D. Del. July 6, 2020).

[2] Thioglycerol or monothioglycerol are used synonymously.

[3] The quote consists of Footnote 6 which notes that “[t]wo claims recite, extra usually, a ‘technique of treating most cancers or malignant illness.’ ’399 patent at claims 13, 15.”