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Formulation and Administration Claims Asserted in Hatch-Waxman Pass Muster

In Cephalon, Inc. v. Slayback Pharma Ltd. Liab. Co., the Federal Circuit summarily affirmed under Rule 36 the district court’s decision that all asserted claims of the asserted patents 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 Pharmaceuticals Int’l GmbH, Cephalon, and Eagle Pharmaceuticals sued Apotex, Fresenius Kabi USA, Mylan Labs., and Slayback Pharma under the Hatch-Waxman Act, 35 U.S.C. § 271(e)(2)(A). Defendants had filed Abbreviated New Drug Applications (“ANDAs”) to market generic versions of Bendeka®. Bendeka®‘s active ingredient is bendamustine hydrochloride (referred to by the parties as bendamustine). The patents at issue were 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 were invalid for obviousness, indefiniteness, lack of enablement, and lack of written description.

District Court Decision

Formulation Claims Not Shown to Have Been Obvious

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

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

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

  3. the solvent polyethylene glycol (PEG);

  4. one of the 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 amount of an antioxidant.

Two claims also specify components and quantities: (1) claim 11 of the ’797 patent requires that “the antioxidant is thioglycerol or monothioglycerol,”[2]and (2) claim 5 of the ‘831 patent requires that “the bendamustine concentration is from about 25 mg/mL to about 50 mg/mL.” Certain claims of the ‘831 and ’797 patents also recite stability limitations such as “less than or equal to 0.11% PG esters at about 1 month of storage at about 5°C.”

Although the district court agreed that “a POSITA would have had reason to try to develop a non-aqueous liquid bendamustine formulation,” the district court was not persuaded that “a POSITA would have used in that formulation the PEG and PG solvents, PEG:PG ratios, antioxidant, concentrations of bendamustine, or PG ester stability limitations recited in the asserted claims.” Id. at 605−06. In fact, the court found that one reference, Drager “taught away from using protic solvents, such as PEG and PG, with bendamustine.” Id. at 607. While Defendants argued that “Alam’s disclosure of mixing cyclophosphamide with PEG and PG would have motivated a POSITA to use those solvents with bendamustine,” the court also found that Alam would not have been considered because it “concerned a compound that degrades differently than bendamustine when combined with PEG and PG.” Id. at 608. In addition, the references did not make the recited PEG:PG ratios obvious, and “the liquid bendamustine examples in Defendants’ prior art references do not include antioxidants” as required by the claims. Id. at 609. The concentration and stability limitations were similarly not shown to be obvious by the asserted references. Id. at 609−11. The inherency argument failed with respect to the stability limitation because the property could not be inherently obvious when the combination itself was not shown to be obvious. Id. at 611.

Administration Claims Not Shown to Have Been Obvious

The asserted administration claims (claims 11, 18, and 22 of the ’568 patent; claim 13 of the ’887 patent) recite methods of treating CLL or NHL6with a liquid bendamustine composition. [3]Certain 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 claim requires a bendamustine dose of “about 25 mg/m2to about 120 mg/m2.” The asserted administration claims also specify administration times, the longest time being “about 15 minutes or less,” and administration volumes that are all 100 mL or less. Finally, certain claims specify post-dilution bendamustine concentrations ranging from 0.05 mg/mL to 12.5 mg/mL.

The district court concluded that “Defendants did not establish by clear and convincing evidence that a POSITA would have been motivated to combine the prior art references to arrive at the claimed administrations with a reasonable expectation of success.” Id. at 614. Although the district court found that the “prior art would have motivated a POSITA to reach the claimed formulation, dose, and dosing schedule,” other limitations were not shown to be obvious. Id.

“It is undisputed that a POSITA would have wanted to use a stable and ready-to-use formulation as part of an improved administration method[,]” but Defendants did not prove that a POSITA would have been motivated to use the asserted prior art to achieve shorter administration times, lower volumes, and higher concentrations. Id. at 614−19. Defendants’ argued that Eagle’s discussion of one of the prior art references in submissions to the FDA would provide the requisite motivation. The district court rejected this argument since the FDA submission was filed after the priority dates of the claims and risked being “distorted by hind-sight bias.” Id. at 619.

Plaintiffs submitted objective evidence of non-obviousness: skepticism, long-felt need, commercial success, and industry praise. But the court did not find it persuasive. Id. at 619−21. Like the formulation claims, however, the district court based its nonobviousness conclusion on the failure of Defendants to establish by clear and convincing evidence that a POSITA would have had reason to combine the prior art references to arrive at the claimed administrations with a reasonable expectation of success. Id. at 620.

Formulation Claims Not Shown to Be Indefinite

Defendants argued that “the claims recite a ‘stabilizing amount’ [of antioxidant] with no guidance, functional or otherwise, on what degree of stability is required to obtain some unnamed objective.” The district court disagreed, finding that Defendants’ argument “conflates (1) whether a given antioxidant amount improves bendamustine’s stability with (2) the extent to which that given antioxidant amount improves stability. Id. at 621−22.

The written description defines a “stabilizing amount of antioxidant” as an amount that “increase[s] or enhance[s] the stability of the bendamustine in the compositions described herein[.]” Id. at 622. Plaintiffs submitted expert testimony that “a POSITA would understand that a stabilizing amount of an antioxidant includes any amount that decreases the amount of bendamustine degradation after any time period and at any temperature.” Id. at 622−23. The specification provides a method for measuring stability and also lists “suitable antioxidant amounts” and “antioxidants,” and provides examples of “stabilizing” amounts. Id. at 623.

Formulation Claims Not Shown to Lack Enablement

Defendants argued that the asserted formulation claims were invalid for lack of enablement because there was no disclosure of “the use of sodium hydroxide (NaOH) or of ‘other undisclosed variables,’”and “a pH adjuster like NaOH is necessary to obtain the PG ester levels claimed in the [a]sserted [f]ormulation [c]laims.” Id. But the district court noted that, without more, the fact that some claimed formulations did not meet all of the claimed limitations was insufficient to show lack of enablement. Id. Defendants presented no evidence that a POSITA would have to undergo undue experimentation to obtain a formulation that met the claim limitations. Id.

Formulation Claims Not Shown to Lack Written Description Support

Defendants argued an asserted claim was invalid for lack of written description based on the same “absence of any mention of a pH adjuster like NaOH . . . demonstrates that the inventors did not have possession of it at that time.” Id. But the district court did not accept that such absence meant “the asserted formulation patents [to] claim something that they do not describe in their written descriptions.” Id. at 624.

Infringement

Defendants stipulated to infringement of the asserted claims with two exceptions: (1) the ANDA products do not contain the “stabilizing amount of an antioxidant” required in the formulation claims; and (2) their proposed labeling does not direct physicians to store their ANDA products for about 3 months at about 25°C. Id.

The district court found that “Defendants’ ANDA products each contain 5 mg/mL of the antioxidant monothioglycerol, . . . and the formulation patents’ written description shows that 5 mg/mL of monothioglycerol is a stabilizing amount.” Id. at 625.

With respect to the proposed label, the district court did not agree with Defendants’ characterization of the issue. The court found that “even though Defendants’ labeling does not mention storage, Defendants’ ANDA products directly and indirectly infringe claim 9 because the PG ester limitation does not require the user to store the products for three months at 25°C. Claim 9′s PG ester limitation describes a characteristic of the claimed formula; it is not a method step and thus, does not require action to infringe. The claim does not recite testing for the PG ester limitation; it just describes a composition that would have less than 0.43% PG esters if one were to test for them after storing the composition for three months at 25°C.” Id. at 625−26. With respect to induced infringement, the court further found that “Defendants will encourage others to administer their ANDA products through their proposed labels. Although Defendants’ proposed labeling does not mention the claimed PG ester limitations, Defendants know ‘that [their ANDA products] meet all of the claim limitations and, through [their] proposed label[s], encourage[] patients to administer [their ANDA products] in a manner that infringes the claimed method.’” Id. at 626.

Take-aways

The burden of establishing a prima facie case of obviousness rests with the party asserting invalidity. This case is a reminder that a case may be decided on the grounds that a prima facie case is not established. When responding to a prima facie case, two options exist: A patent owner can either provide arguments undercutting one or more of its criteria (i.e., “attacking the prima facie case”) or submit evidence of nonobviousness (i.e., “rebutting the prima facie case”). In attacking the prima facie case, the practitioner may argue (1) that a prior art reference cannot be properly modified or combined with other references, because, in view of the scope and content of the prior art and the level of ordinary skill, the claimed invention was not obvious, and/or (2) that even if modified or combined as proposed, a POSITA would have no basis for a reasonable expectation of success. 

This case also reminds practitioners that expert testimony as to what a POSITA would understand may be helpful against §112 invalidity assertions.


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

[2] Thioglycerol or monothioglycerol are used synonymously.

[3] The quote includes Footnote 6 which notes that “[t]wo claims recite, more generally, a ‘method of treating cancer or malignant disease.’ ’399 patent at claims 13, 15.”

© 2022 Finnegan, Henderson, Farabow, Garrett & Dunner, LLPNational Law Review, Volume XI, Number 312
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Paul W. Browning Patent Attorney Finnegan Washington DC
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Paul Browning, Ph.D., is a first chair litigator focusing on patent litigation and appeals, primarily in the chemical and pharmaceutical areas, including Hatch-Waxman litigation. He has tried cases before judges in various U.S. district courts and has handled arbitrations and mediations. He also advises on patent portfolio strategy with an eye toward success in litigation.

Paul’s broad litigation experience includes taking and cross-examining witnesses at trial, briefing and arguing dispositive motions, drafting appellate briefs, and arguing...

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Misook Kim Patent Attorney Finnegan Palo Alto, California
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Misook Kim focuses her practice on patent prosecution, primarily in the computer and electrical technology areas.

Prior to joining Finnegan, Misook obtained significant patent experience working for over 10 years as a Korean patent attorney, handling a wide range of matters, including prosecution, trials, and opinions on patentability, infringement, and validity. She assisted clients with counseling, patent mining, and global management of their patent portfolios. Her practice focused mainly on computer architecture, wireless network, mobile...

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Emma Ng is an associate attorney in Finnegan’s Washington, DC office. She graduated from the  Indiana University Maurer School of Law in 2021.

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Thomas L. Irving Intellectual Property Finnegan, Henderson, Farabow, Garrett & Dunner Washington, DC
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Tom Irving has some 45 years of experience in intellectual property law. His U.S. pharma practice includes America Invents Act (AIA) post-grant proceedings, due diligence, counseling, patent prosecution, reissue, and reexamination. In addition to advising on procuring strong U.S. patents, Tom counsels clients on a wide range of mainly pharmaceutical matters, including pre-litigation, Orange Book listings of patents covering FDA-approved drugs, infringement issues, enforceability, supplemental examination, and validity analysis. He has served as lead counsel in numerous patent interferences...

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