Bendamustine - USA

On Apr 27, 2020, Delaware court found Eagle pharmaceuticals patents valid & infringed by ANDA filers.

Plaintiffs (Teva, Cephalon and Eagle Pharmaceuticals) sued Defendants (Apotex, Fresenius Kabi, Mylan, and Slayback Pharma) as they sought to bring to market generic versions of Plaintiffs' Bendeka®, a drug indicated for the treatment of chronic lymphocytic leukemia (CLL) and indolent B-cell nonHodgkin lymphoma (NHL). Plaintiffs alleged infringement of U.S. Patent Nos. 9,265,831, 9,572,797 (formulation patents) and  9,144,568, 9,597,399, 9,572,887 (administration patents). Defendants mostly stipulated to infringement of the asserted claims (except two) and argued that all asserted claims are invalid.

Obviousness:

      1.   Formulation patents:

The main components of the asserted formulation are: 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," 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 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.

Bendamustine is prone to degradation because of two functional groups (a nitrogen mustard group and a carboxylic acid group). Because water causes bendamustine to degrade at its nitrogen mustard group, the prior art bendamustine formulations used a lyophilized (freeze-dried) form of bendamustine that required a human operator to reconstitute it using water shortly before administering it to a patient. But this reconstitution by human manipulation had two known disadvantages: it increased the risk of contamination and, because bendamustine is a cytotoxic compound, it posed a potential danger to the operator. Inventor of the asserted patents overcame this problem by providing stable non-aqueous bendamustine composition which contains appropriate quantities of PG & PEG solvents.

Defendants argued that five prior art references would have motivated a POSITA to arrive at the asserted formulation claims with a reasonable expectation of success: Olthoff, Drager, Alam, Rowe, and Boylan.

Olthoff (1983) – discloses non-aqueous, ready to use bendamustine formulation (25 and 100 mg/mL) in polyols such as PG & PEG. Olthoff's examples did not use an antioxidant.

Drager (2008) – discloses stable liquid pharmaceutical formulations comprising bendamustine.But Drager determined that the "results described in [Olthoff] were not reproducible." Drager' s data showed that bendamustine in 99% PG degraded almost completely after eight weeks at 25°C and more than 20% at 5°C after one year.  The reason for that degradation, according to Drager, was that (1) PG causes bendamustine to degrade at the nitrogen mustard group and (2) PG's OH groups cause bendamustine to degrade at the carboxylic acid group through esterification. As a solution to the degradation problem, Drager disclosed the use of aprotic solvents (DMA). Drager also taught that protic solvents-i.e., solvents, including PEG and PG, that have OH groups-are acceptable to use with bendamustine but only when combined with aprotic solvents.

Alam (1989) - disclosed stable liquid formulations of cyclophosphamide, a compound that, like bendamustine, has a nitrogen mustard group & tested its stability in 3 polyols (PG, PEG & glycerols). Alam disclosed using PG at a ratio of from about 10% to about 90% and PEG at a ratio of from about 90% to about 10%.

Rowe -  Rowe's Handbook of Pharmaceutical Excipients disclosed that PEG is susceptible to oxidation and that one can use an antioxidant to prevent such oxidation.

Boylan - Boylan disclosed a list of "some of the most commonly used antioxidants in pharmaceutical injectable formulations" including monothioglycerol.

Defendants argued that Olthoff, Drager, and Alam would have motivated a POSITA to use PEG and PG with bendamustine. Court, however, said that Drager teaches away from Olthoffs teaching of using polyols. Specifically, Drager determined that the results described in [Olthoff] were not reproducible & bendamustine degrades completely in PG after 8 weeks. Drager, therefore, suggested use of aprotic solvent as major component. Drager specifically showed that a formulation containing 66% DMA and 34% PG is stable. Drager, thus, teaches away from the use of only protic solvents (PG & PEG). Therefore, Drager would not have motivated a POSA to replace DMA with a low-OH protic solvent. POSA would have given more weightage to Dragger over Olthoff because data is more reliable in Dragger since it used HPLC & Olthoff used TLC method. Moreover, in the decades between Olthoffs publication in 1983 and the priority date in 2010, Olthoffs formulations were never used, suggesting that POSA generally did not rely on Olthoff. Third reference, Alam is related to cyclophosphamide & the structural differences between bendamustine & cyclophosphamide would have discouraged POSA because degradation pathway would be different. Therefore, POS A would not have viewed cyclophosphamide as a relevant comparator for bendamustine reactions, and would not have considered Alam in formulating a stable bendamustine formulation. In sum, Defendants have not proven by clear and convincing evidence that Olthoff, Drager, and Alam would have motivated a POSITA to use PEG and PG to create a non-aqueous liquid bendamustine formulation.

Since, POSA would not have motivated to use PG & PEG, the other claimed limitations such as PEG:PG ratio, use of antioxidant, bendamustine concentration, stability limitations would not have been obvious. With respect to only argued secondary consideration - “commercial success”,  court said that the evidence of $2 billion sales of Bendeka  does not support a finding of nonobviousness. First, Bendeka® sells at a lower price than the prior art lyophilized Treanda® product. Second, Plaintiffs' cluster of exclusivities has blocked others from entering the market. Court finally held that although the evidence of commercial success does not support a finding of nonobviousness, Defendants have not shown by clear and convincing evidence that the prior art they cited would have motivated a POSIT A to reach the claimed formulations.

      2.  Administration patents:

The asserted administration claims recite methods of treating CLL or NHL with a liquid bendamustine composition. 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/m2 to about 120 mg/m2”. The asserted administration claims also specify administration times, the longest time being "about 15 minutes or less”.They also specify 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.

Defendants argued that eight prior art references would have motivated a POSIT A to combine the elements of the claimed administration with a reasonable expectation of success: Palepu 2011 (Formulation patents as discussed above), the Treanda® Label, Preiss 1985 (PK study with 3 minutes of administration of bendamustine with 280 to 375 mg dose), Preiss 1998 (MTD study with 3 to 10 minutes of administration of bendamustine with 54 to 226 mg/m2 dose), Schoffski 2000a (administration of bendamustine over 30 minutes and compared its results to the three-to-ten-minute infusions disclosed in Preiss 1998), Schoffski 2000b (Schoffski 2000b administered 60 to 80 mg/m2 of bendamustine in 30 minutes), Barth (suggested administering bendamustine in a solvent volume of 100 to 250 mL), and Glimelius (disclosed the administration of 5-Fluorouracil to treat colorectal cancer as an infusion lasting ten to 20 minutes using a 50 to 100 mL mini-bag).

Court said that prior arts would have motivated a POSA to reach the claimed formulation, dose, and dosing schedule. But, the prior arts would not have motivated a POSA to reach the remaining claim limitations (Administration Times, Volumes, and Post-Dilution Concentrations), and thus the claims as a whole are not obvious. All asserted claims require administering bendamustine in 15 minutes or less, with some requiring ten minutes or less. All asserted claims also require administering bendamustine in a volume of 100 mL or less, with some claims requiring about 50 mL. Finally, all but one of the asserted administration claims require post-dilution bendamustine concentrations ranging from 0.05 to 12.5 mg/mL. Defendants argued that the Preiss studies support a finding that the claimed administration times, volumes, and concentrations are obvious. Court, however,found that Preiss studies would not have motivated a POSA to reach the claimed administration times, volumes, or concentrations because (1) a POSA would not have relied on the Preiss studies to determine a safe and effective infusion time, volume, or concentration for bendamustine because those studies were not designed to evaluate safety, (2) subsequent prior art taught away from Preiss's three-to-ten-minute infusions, instead, it would have considered later prior art references that used 30 to 60 minute infusions and a 500 mL volume and (3) Defendants only hypothesize that the Preiss studies used volumes and concentrations similar to those in the claimed administrations, such speculations about Preiss's infusion rate and volume, however, are only based on "conclusory and unsupported expert testimony" and they do not support a finding of obviousness by clear and convincing evidence.

With respect to secondary consideration, Plaintiffs offered at trial evidence of four secondary considerations that bear on the administration claims: skepticism, long-felt need, commercial success, and industry praise. Court, however, did not find this evidence to be probative indicia of nonobviousness.

Indefiniteness:

Defendants argued that the asserted formulation claims are invalid because they each require "a stabilizing amount of antioxidant"-a requirement Defendants contend is indefinite. Specifically, Defendants argued that the term is indefinite because "[t]he specification does not explain how to determine whether stability has been 'increased' or 'enhanced.’ Court, however, disagreed  & said that the patents provide a POSA with a method for measuring stability: using HPLC to compare the amount of overall bendamustine degradation with and without the antioxidant. Example 3 demonstrates that a POSA would compare the amount of bendamustine remaining in the same formulation, stored under the same conditions, with and without the antioxidant. In addition to providing exemplary test methods, the specification also lists "suitable antioxidant amounts" and "antioxidants," and provides examples of "stabilizing" amounts. Court, thus found that the term "stabilizing amount of antioxidant" is not indefinite and court construed it as: any amount of an antioxidant that decreases the amount of bendamustine degradation after any time period and at any temperature.

Enablement:

Defendants asserted that the asserted formulation claims are invalid for lack of enablement because the formulation patents disclosed neither the use of sodium hydroxide (NaOH) or of "other undisclosed variables." Specifically, Defendants argued that the asserted formulation claims are not enabled because the claims do not contain NaOH and "a pH adjuster like NaOH is necessary to obtain the PG ester levels claimed in the [a]sserted [f]ormulation claims. Court said that evidence that some claimed formulations did not result in the PG ester limitations, does not establish that the claims are not enabled. Defendants have not presented any evidence to show that a POSA would have had to undertake undue experimentation to alter the formulation to obtain the PG ester limitations. That some formulations with the claimed ingredients do not satisfy the PG ester limitations does not support non-enablement unless the number of such formulations is significant enough to have required a POSA to experiment unduly. [Atlas Powder, 750 F.2d at 1576-77….Even if some of the claimed combinations were inoperative, the claims are not necessarily invalid ....)]. Accordingly, Defendants failed to establish by clear and convincing evidence that the asserted claims are invalid for lack of enablement.

Lack of written description:

Apotex argued that claim 9 of the #797 patent is invalid for lack of written description. It asserted that "the absence of any mention of a pH adjuster like NaOH in the [#]797 patent demonstrates that the inventors did not have possession of it at that time, as confirmed by their later filing of another patent application that discloses and claims it." Court said that "written description is about whether the skilled reader of the patent disclosure can recognize that what was claimed corresponds to what was described .... ["Alcon Research Ltd. v. Barr Labs., Inc., 745 F.3d 1180, 1191 (Fed. Cir. 2014)]. And Apotex never citeed the intrinsic record to show that the asserted formulation patents claim something that they do not describe in their written descriptions. Instead, Apotex improperly cited extrinsic evidence-the later-filed Eagle patent application. Apotex has thus failed to establish that claim 9 is invalid for lack of written description.

Infringement:

Defendants stipulated to infringement of the asserted claims with two exceptions. Apotex, Fresenius Kabi, and Mylan argued that (1) they do not infringe the asserted formulation claims because their ANDA products do not contain "a stabilizing amount of an antioxidant" as the asserted formulation claims require, and (2) they do not directly infringe or induce infringement of claim 9 of the #797 patent, which requires that the "bendamustine-containing composition ha[ve] less than or equal to 0.43 % total PG esters at about 3 months of storage at a temperature of about 25°C," because their proposed labeling does not direct physicians to store their ANDA products for about 3 months at about 25°C.

With respect to first point, court said that it has construed the term as any amount of an antioxidant that decreases the amount of bendamustine degradation after any time period and at any temperature. 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. The written description identifies "5 mg/mL to about 20 mg/mL" as a "preferable" stabilizing amount of antioxidant. Moreover, Example 3 demonstrates that adding "5 mg/m[L] of lipoic acid ... as a stabilizing antioxidant" to 20 mg/mL of bendamustine in PEG decreased the amount of bendamustine degradation after 15 days at 25°C and 40°C as compared to the same formulation without an antioxidant. Moreover, Fresenius Kabi and Mylan represented to the FDA that 5 mg/mL monothioglycerol was sufficient to ensure that the amount of bendamustine in their ANDA products did not fall below specification limits.

With respect to second point,  Defendants stipulated that their ANDA Products have "less than or equal to 0.43% total PG esters at about 3 months of storage at a temperature of about 25° C," but contend that they do not directly infringe or induce infringement of claim 9 because their proposed labeling does not recommend storing their ANDA Products for "about 3 months" at "a temperature of about 25° C." Court, however, said 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. Therefore, Defendants infringe and induce infringement of each of the asserted claims.