Cinacalcet - USA

On Jan 07, 2020, Federal Circuit affirmed district court’s decision as to Piramal, Zydus & vacated as to Amneal as district court erred in claim construction.

Amgen is NDA holder for Sensipar®(cinacalcet hydrochloride) used to treat secondary hyperparathyroidism in adult patients with chronic kidney disease who are on dialysis and to treat hypercalcemia in patients with parathyroid cancer and primary and secondary hyperparathyroidism. Amneal, Piramal, and Zydus each filed ANDA seeking to enter the market with a generic version of Sensipar®. Amgen brought suit against each ANDA filer alleging infringement of US 9,375,405 patent. Amgen asserted different claims against each defendant, but the parties stipulated that the infringement findings for claim 1 would extend to the majority of the remaining claims.

Claim 1 reads:

A pharmaceutical composition comprising:

(a) from about 10% to about 40% by weight of cinacalcet HCl in an amount of from about 20 mg to about 100 mg;

(b) from about 45% to about 85% by weight of a diluent selected from the group consisting of microcrystalline cellulose, starch, dicalcium phosphate, lactose, sorbitol, mannitol, sucrose, methyl dextrins, and mixtures thereof,

(c) from about 1% to about 5% by weight of at least one binder selected from the group consisting of povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, and mixtures thereof; and

(d) from about 1% to 10% by weight of at least one disintegrant selected from the group consisting of crospovid[o]ne, sodium starch glycolate, croscarmellose sodium, and mixtures thereof,

wherein the percentage by weight is relative to the total weight of the composition, and wherein the composition is for the treatment of at least one of hyperparathyroidism, hyperphosphonia, hypercalcemia, and elevated calcium phosphorus product.

District Court decision:

In the district court litigation, the construction of the binder and disintegrant Markush groups was a key issue. Amgen argued that the Markush groups should be open to unrecited elements, but the district court disagreed. Relying on “Multilayer Stretch Cling Film Holdings, Inc. v. Berry Plastics Corp., 831 F.3d 1350 (Fed. Cir. 2016)”, the court held that “Amgen ha[d] not overcome the very strong presumption that the Markush groups for the binder and disintegrant elements are closed to unrecited binders and disintegrants.” The district court held a bench trial on the issue of infringement. The court held that Amneal and Piramal do not infringe any claim of the ’405 patent but found that Zydus infringes. First, the district court found that Amneal does not infringe the asserted claims because its product does not meet the binder limitation. As a binder, Amneal uses Opadry Clear YS-1-7006, a product that contains hydroxypropyl methylcellulose (“HPMC”), polyethylene glycol 400, and polyethylene glycol 8000. Although HPMC is a listed binder, the court found that Opadry itself is not, so Amneal does not literally meet the binder limitation. Next, the district court found that Piramal does not infringe because it does not meet the binder limitation. Piramal uses pregelatinized starch which is not recited in claim. Amgen argued that the cold-water soluble fraction of the starch is equivalent to povidone, a listed binder. But the court rejected this argument as barred by prosecution history estoppel. During prosecution Amgen had narrowed its claims by accepting the Examiner’s Amendment to exclude binders different from those listed in the Markush group. In contrast, the district court found that Zydus’s ANDA product infringes the asserted claims. At issue for Zydus was the function of the pregelatinized starch in its formulation. Zydus’s ANDA states that the formulation uses pregelatinized starch as a diluent, and starch is listed in the diluent Markush group of claim 1. Zydus relied on testimony from Dr. Davies, Amgen’s expert,  that the cold-water soluble fraction of pregelatinized starch could function as an unlisted binder, but the court disagreed & found infringement.

Federal Ciruit decision:

Amgen appealed from the district court’s judgment that Amneal and Piramal do not infringe the ’405 patent. Zydus cross-appealed from the district court’s judgment that it infringed.

Amgen first challenged the district court’s construction of the binder and disintegrant Markush groups in, respectively, elements (c) and (d). The district court held both of these Markush groups to be closed. In reaching this result, the district court first compared claim 1 to that at issue in Multilayer, which similarly recited “comprising,” followed by “consisting of” terminology. The court explained that, as in Multilayer, there was a “very strong presumption” that the Markush groups were closed to unrecited constituents. Amgen argued that the “comprising” term renders the claim open-ended, even when other language restricts the scope of particular claim elements, and the “consisting of” term here only applies to the group from which “at least one” binder or disintegrant must be selected. Amgen also contrasts the binder and disintegrant limitations with the diluent limitation, which lacks the “at least one” language. Amgen maintains that the “at least one” language would be meaningless if the groups are closed to additional binders and disintegrants and meaningless in view of the claim’s recitations of “mixtures thereof” within the Markush groups. Amgen argues that its claims here are distinguishable from the Multilayer claims at issue in those cases because of the “at least one” limitation.

Federal Circuit said that defendants read more into Multilayer decision. Multilayer did not hold broadly that, whenever “consisting of” Markush group language is present in a particular claim limitation, even when the limitation follows a general claim transition phrase of “comprising,” all components of an accused product that perform the general function of the particular limitation must meet the requirements of that limitation, thus precluding components outside the Markush group. No such issue was presented in those cases. Rather, each decision held only that the terms of a particular claim limitation that used “consisting of” Markush group language were restricted to members of the Markush group. Those decisions do not apply in this case, where the question is whether the “binder” or “disintegrant” claim limitations are written to preclude other binders and disintegrants in the claimed composition.

The decisive issue in this case is critically different from any issue decided in Multilayer or Shire. The issue is whether all binders or disintegrants in the claimed formulation are subject to the specific binder or disintegrant limitations. Federal Circuit further said that there is no language in Amgen’s claim indicating that every binder or disintegrant in the claimed formulation must be within the Markush groups. Instead, the claim recites “at least one” binder or disintegrant “selected from the group consisting of” various excipients. And the limitations merely require that those particular binders or disintegrants meet the specified weight-percentage requirements, which is not inconsistent with the overall composition containing other binders or disintegrants. The plain language of this claim requires “at least one” of the Markush members and certainly does not indicate that the only binders and disintegrants in the claimed formulation are those listed in the groups.

Importantly, claim requires “comprising” language which means the claim does not preclude the presence of unrecited components or steps. Amgen’s use of the “comprising” transition phrase reinforces the conclusion that the language of those limitations is best construed not to foreclose such additional binders and disintegrants. Thus, optional additional binders and disintegrants not recited in the Markush group may be included in the claimed formulation. Without more, such language is satisfied when an accused product contains a component that is from the Markush group and that meets the limitation’s requirements for the component. It does not forbid infringement of the claim if an additional component is present functionally similar to the component identified in the Markush group limitation, unless there is a further basis in the claim language or other intrinsic evidence for precluding the presence of such additional components. Because the district court’s claim constructions in this case excluded formulations with additional unlisted ingredients—binders, disintegrants, or otherwise—those constructions are incorrect.

Now coming to Amneal’s product, Federal Circuit said that it uses “Opadry” as a binder. Opadry is a composite product comprised of HPMC, polyethylene glycol (“PEG”) 400, and PEG 8000. By containing Opadry, Amneal’s formulation necessarily contains HPMC. HPMC is a binder listed in the binder Markush group of claim 1, so, provided that Amneal’s formulation contains from about 1% to about 5% HPMC, irrespective of whether PEG is present, the formulation literally meets the binder limitation of claim 1.  There will of course be differences between HPMC alone as compared to Opadry, which is HPMC combined with PEG. But those differences cannot alter the conclusion that HPMC is present in Amneal’s formulation, even if it was added as a component of another commercially available product. The claim requires only that HPMC be present, not that HPMC’s physical characteristics or function be unaffected by additional ingredients. Federal Ciruit thus vacated & remanded asking district court to consider whether Amneal’s formulation contains “from about 1% to about 5% by weight” of HPMC, irrespective of the HPMC’s pairing with PEG.

With respect to Piramal’s product, Federal Circuit sided with district court & said that it correctly applied prosecution history estoppel. Piramal’s product uses pregelatinized starch as a binder, which is not listed in the binder Markush group of claim 1. Amgen during appeal argued that under the doctrine of equivalents that pregelatinized starch has a native starch fraction that functions as a diluent and a cold water soluble fraction that functions as a binder. But court court rejected Amgen’s doctrine of equivalents argument as barred by prosecution history estoppel. During prosecution, the examiner rejected Amgen’s claims for obviousness, and, in response, Amgen narrowed the the claim in an attempt to overcome the rejection. Piramal argued that Amgen’s acceptance of the Examiner’s Amendment led directly to the allowance of the claims. Piramal also argued that the addition of the Markush groups overcame the obviousness rejection. Court agreed with Piramal & held that Amgen’s doctrine of equivalents argument is barred by prosecution history estoppel.

With respect to Zydus’ product, Federal Circuit sided with district court & said that Zydus’s ANDA states that the pregelatinized starch in Zydus’s formulation functions as a diluent which is one of the claimed diluent.  Zydus argued that the starch also functions as a binder. To support its position, Zydus adopted the testimony of Dr. Davies, Amgen’s expert, that Amgen had proffered for its argument about Piramal’s formulation. Dr. Davies opined that pregelatinized starch’s native starch fraction functions as a diluent but that its cold water soluble fraction functions as a binder. But district court did not find Dr. Davies’s testimony credible for several reasons & found that Zydus’s ANDA product infringed claim 1. Federal Circuit thus agreed with district court & Amgen that the district court did not clearly err in finding that the pregelatinized starch in Zydus’s product functions as a diluent.