Cinacalcet - USA

On Jul 27, 2018, District of Delaware delivered opinion in Sensipar® Hatch-Waxman litigation & found Amneal, Piramal, Watson non-infringing & Zydus infringing.

This is a consolidated patent infringement action in which Amgen accuses multiple Defendants of infringing US 9,375,405 patent by filing ANDA seeking FDA approval to manufacture, use and/or sell generic versions of Sensipar®. These Defendants are Amneal, Piramal, Watson & Zydus. Court bifurcated the infringement claims and invalidity counterclaims and held a four-day bench trial on infringement beginning on March 5, 2018. The ’405 patent relates to “Rapid Dissolution Formulation of Calcium Receptor-Active Compound”. For most of the asserted claims, the parties’ stipulated that a finding of infringement would depend on the findings for claim 1 of the ’405 patent. Claim 1 recites a pharmaceutical composition combining specific excipients in specific amounts with the active ingredient cinacalcet hydrochloride.

Claim 1 of the ’405 patent specifically states:

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 crospovidine (sic), 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.

On February 27, 2018, court construed the Markush groups for the binder and disintegrant elements as “closed to unrecited binders and disintegrants.” Court concluded that “there could be no literal infringement if the Defendants’ ANDA product contained an unrecited (or unlisted) binder or disintegrant.” Amgen then opposed the court’s construction of the Markush groups by filing a motion for reargument, which was later denied.

Amneal product:

Amneal’s ANDA contains Opadry YS-1-7006 (“Opadry”) as binder. But claim 1 of the ’405 patent does not list Opadry in the Markush group for binders, therefore there was not a clear case of literal infringement. Amgen nonetheless attempted to prove literal infringement by arguing that Opadry is a pseudonym for hydroxypropyl methylcellulose (“HPMC”), which is a listed binder. Alternatively, Amgen argued that infringement is established through the doctrine of equivalents. Court disagreed with Amgen on both of these arguments. Court concluded that for numerous reasons the Opadry is not literally HPMC. The excipients have different chemical structures, physical characteristics, binding mechanisms, and commercial sources.  Amneal also does not infringe the binder limitation under the doctrine of equivalents. Here, Amgen’s expert, Dr. Davies, opined in conclusory fashion that only the HPMC fraction of Opadry functioned as the binder, and “the polyethylene glycol … in the Opadry doesn’t act as a binder.” Dr. Davies never explained it with “function-way-result,” or “substantial/insubstantial differences” test. The court is therefore not obligated to accept the conclusory assertions of an expert. Thus, Dr. Davies’ opinion, given without explanation or corroborating evidence, was not found persuasive.

Amneal’s ANDA discloses the use of the listed disintegrant crospovidone and the unlisted disintegrant pregelatinized starch. The ’405 patent lists “starch” in the Markush groups for diluents, and the parties remaining in this litigation do not dispute that the term “starch” in the ’405 patent covers pregelatinized starch. Accordingly, Amgen argued that the pregelatinized starch in Amneal’s product is not functioning as a disintegrant, but as a diluent. Amgen’s sole support for its argument is Dr. Davies’ opinion that crospovidone is a super-disintegrant which destroys the structure of a tablet so quickly that the pregelatinized starch does not have the opportunity to act as a disintegrant. However, court did not find Dr. Davies’ opinion, as applied to Amneal’s ANDA product, convincing. First, as Dr. McConville (Amneal’s expert) testified, Amneal’s ANDA product does not appear to need another diluent. Amneal’s ANDA product already includes two diluents—microcrystalline cellulose and mannitol—in a large amount; specifically, 67.89% by weight of the accused product. Second, Dr. McConville persuasively testified that, with Amneal’s manufacturing process, the crospovidone cannot usurp the disintegration function of the pregelatinized starch. Here, Amneal uses pregelatinized starch as an intragranular disintegrant and crospovidone as an extragranular disintegrant. And because the pregelatinized starch is the only disintegrant inside the granules, it alone acts as a secondary disintegrant. Third, Amneal’s ANDA contains the results of testing which confirm that the pregelatinized starch in its product functions as a secondary disintegrant.

Thus, Amgen has failed to show by a preponderance of the evidence that Amneal’s accused product infringes the binder and disintegrant limitations of the ’405 patent. For the foregoing reasons, Amneal does not infringe claim 1 of the ’405 patent. This means, pursuant to the parties’ stipulation, Amneal does not infringe claims 2-4, 8-12, and 14-17.

Watson product:

Watson uses unlisted disintegrant, low substituted hydroxypropyl cellulose (“L-HPC”), which under court’s claim construction order means there is no literal infringement. As a result, Amgen argued that L-HPC infringes claim 1 under the doctrine of equivalence. At trial, Amgen took the position that L-HPC is equivalent only to crospovidone and only under the function-way-result test. However, in its post-trial briefs, Amgen took two new positions: (1) L-HPC is equivalent to all three listed disintegrants of claim 1 under the function-way-result test, and (2) L-HPC is equivalent to crospovidone under the insubstantial differences test. Watson correctly pointed out that Amgen did not fairly presented these positions in expert discovery or at trial. For that reason alone, Amgen’s new infringement theories should be disregarded as an unfair surprise. Court however, still found why Amgen’s new theories under the function-way-result test are not persuasive & explained why Amgen’s original theory also would have failed.

Court said that Amgen should have presented through its expert, Dr. Davies, particularized testimony regarding the function, way, and result for each disintegrant to be compared. Dr. Davies, however, did not identify at trial what he considered to be the function, way, or result of the disintegrants being compared. Accordingly, Amgen failed to prove at trial that L-HPC is equivalent under the function-way-result test to all three disintegrants listed in claim 1. Also because L-HPC is not a superdisintegrant, it does not perform substantially the same function as the disintegrants listed in claim 1. In addition, Dr. Davies’ testimony on this point was unclear: He also testified that “there are a number of different mechanisms by which [superdisintegrants] work.” Amgen also argued that L-HPC is equivalent to crospovidone under the insubstantial differences test. Amgen’s expert, Dr. Davies, did not provide an opinion regarding the insubstantial differences between L-HPC and crospovidone. Dr. Appel (Watson;s expert)identified several differences between L-HPC and crospovidone, which were corroborated by scientific literature.

Thus, Amgen has failed to prove by a preponderance of the evidence that L-HPC is equivalent to all of the disintegrants listed in claim 1 under the function-way-result test or that L-HPC is equivalent to crospovidone alone under the insubstantial differences test. Therefore, Watson does not infringe claim 1 of the ’405 patent. This means, per the parties’ stipulation, Watson does not infringe claims 2-4, 8-17, and 19-20.

Piramal product:

The parties disputed whether Piramal’s ANDA product infringes the binder and disintegrant limitations of claim 1. Amgen argued that the unlisted binder in Piramal’s ANDA product—pregelatinized starch—has two components; a native starch fraction that actually functions as a diluent; and a cold water soluble fraction that functions as a binder. Neither pregelatinized starch nor its cold water soluble fraction are listed in the Markush group for binders, which under court’s claim construction order means there is no literal infringement. Accordingly, Amgen argued that cold water soluble fraction is equivalent to povidone. But court found that Amgen is foreclosed by prosecution history estoppel from asserting the doctrine of equivalents against Piramal’s use of pregelatinized starch as a binder.

During prosecution, Examiner did not allow the claims in the 2014 Amendment which included specific 20-100 mg of cinacalcet. Instead, the Examiner proposed the Examiner’s Amendment, which added the Markush groups to the binder and disintegrant limitations. In addition, the Examiner expressly stated that he was allowing the claims as set forth in the Examiner’s Amendment because, inter alia, the closest prior art “fails to specifically disclose or render obvious the combination of components and in the amounts thereof.” For all of these reasons, court found that the Examiner’s Amendment was adopted for substantial reasons related to patentability & hence estoppel applies.

Thus, for the foregoing reasons, Amgen cannot prove that Piramal’s product infringes claim 1 of the ’405 patent. Per the parties’ stipulation, Piramal also does not infringe claims 2-4, 8-17, and 19-20.

Zydus product:

Amgen’s dispute with Zydus comes down to the function of pregelatinized starch. Amgen took the position that it functions as a diluent, as stated in Zydus’ ANDA. Zydus takes the position that it functions as a binder. Zydus’ position adopts an opinion Amgen’s expert has asserted against other defendants. In tablet formulations, pregelatinized starch can, depending on the context, function as a diluent, binder, or disintegrant. The ’405 patent, however, limited itself by claiming pregelatinized starch only as a diluent. On the face of the ANDA, Zydus’ product appears to literally infringe each and every limitation of claim 1. To avoid a finding of literal infringement, Zydus simply adopted Dr. Davies’ opinion that the cold water soluble fraction of pregelatinized starch functions as an unlisted binder. Normally, where literal infringement is unavailable, a patentee can still prove infringement by resorting to the doctrine of equivalents. Here, however, court granted a motion in limine, which bars Amgen from asserting the doctrine of equivalents against Zydus.

Court was not persuaded that Dr. Davies’ opinion regarding pregelatinized starch is scientifically sound. Amgen claims that three defendants literally infringe claim 1, because the fractions opinion applies to Aurobindo and Piramal but not to Zydus. But Dr. Davies could not provide a credible explanation for this variation in treatment. First, he said that the pregelatinized starch in Zydus’ product functioned only as a diluent, because that was how Zydus identified the pregelatinized starch in its ANDA. When it was pointed out that Dr. Davies did not accept how pregelatinized starch was identified in other defendants’ ANDAs, he agreed and said that was why he was also asserting his fractions opinion against Zydus. This shift in infringement theories does not place Amgen in a better position. Amgen acknowledges, Zydus already uses 4.98% of hydroxy propyl cellulose as a binder. If the cold water soluble fraction in Zydus’ product also acts a binder, then that is another 3.97% acting as a binder. Adding 4.98% of hydroxy propyl cellulose to 3.97% of a cold water soluble fraction results in a total 8.95% of binder, which exceeds the “about 5%” weight limitation in the ’405 patent. When Zydus raised this point with Dr. Davies, he shifted infringement theories yet again, stating that Zydus’ product literally infringed the binder limitation, because there was “at least one” binder from the Markush group in Zydus’ product that was within the about 1% to about 5% weight limitation: the 4.98% of hydroxy propyl cellulose. This testimony is not consistent with the court’s controlling claim construction. Ultimately, Dr. Davies consistently asserted, and other experts agreed, that the particular function of pregelatinized starch in any given formulation “depends on the context,” including the amount of pregelatinized starch, the other excipients present, and the manufacturing process. When evaluating the ANDA products for Amneal, Piramal, and Zydus, the percolation theory provides the consistency lacking in Dr. Davies’ opinion. For example, Amneal and Zydus use over 20% by weight of pregelatinized starch which is consistent with the diluent function identified in their ANDAs. Piramal uses 11% of pregelatinized starch which is consistent with the binder function identified in its ANDA. Finally, the Example uses 33.378% of pregelatinized starch which is consistent with a diluent function that would result in the ’405 patent covering the Example.

Given all of the foregoing, Court found that Amgen has not proven by a preponderance of the evidence that pregelatinized starch should be artificially divided into two fractions, with each fraction alone serving a different function. As a result, Zydus cannot defeat Amgen’s assertions of literal infringement by adopting Dr. Davies’ opinion that the cold water soluble fraction of pregelatinized starch functions as a binder. Zydus’ ANDA product literally infringes claim 1 to the extent the claim is found valid and enforceable. Court also found per the parties’ stipulation that Zydus’ ANDA product literally infringes claims 2-4, 8-9, 15-17, and 19, to the extent each claim is found valid and enforceable.