Apixaban - USA

On Aug. 05, 2020, Delaware Court found compound and composition patents valid & infringed by ANDA filers.

Bristol-Myers Squibb / Pfizer Inc. (Plaintiffs) sued Sigmapharm Laboratories, Sunshine Lake Pharma and Unichem Laboratories (Defendants) under Hatch-Waxman Act as Defendants filed ANDAs to market generic version of Eliquis® [All other, at least 22 Defendants resolved their disputes before trial]. Plaintiffs sued Defendants for infringement of US 6,967,208 (compound patent – expiring on 11/21/2026) and US 9,326,945 (composition patent – expiring on 02/24/2031). Defendants brought counterclaims alleging that the asserted claims of both the '208 (claims 13 and 104) and '945 (claims 21 and 22) patents are not infringed and invalid. The Court held a nine-day bench trial between October 23 and November 13, 2019.

Asserted claims (US’208): Claim 13 which is a dependent claim recites apixaban or a pharmaceutically acceptable salt form of apixaban. Claim 104 which is dependent on claim 13 recites crystalline apixaban.

Asserted claims (US’945): Claims 21 and 22 (recites dose of apixaban as 2.5 mg & 5 mg respectively) depend on claim 12 which is:

12. A solid pharmaceutical composition comprising a therapeutically effective amount of apixaban and a pharmaceutically acceptable diluent or carrier, wherein apixaban comprises crystalline apixaban particles, wherein the crystalline apixaban particles have a D.sub.90 equal to or less than about 89 µm, and wherein, as measured using a USP Apparatus 2 at a paddle rotation speed of 75 rpm in 900 mL, of a dissolution medium at 37.degree. C., at least 77 wt % of apixaban in the pharmaceutical composition dissolves within 30 minutes in the dissolution medium, and the dissolution medium is 0.05 M sodium phosphate at a pH 6.8 containing 0.05% sodium lauryl sulfate.

Infringement:

1. Sigmapharm’s ANDA:

Sigmapharm used crystalline Form I of apixaban as the starting material for manufacturing of apixaban tablet. It used process where crystalline Form I was dissolved in solution with povidone & then it was sprayed, dried to make amorphous solid dispersion.  

With respect to US’208 patent, Sigmapharm argued that claim 1 of the patent on which claim 13 & claim 104 depend does not cover apixaban. Claim 1 requires that particular rings are “substituted with” certain number of R groups. Sigmapharm contended that each of these limitations specifies how many hydrogen atom “substituents” can be included in each ring.  BMS countered that it requires only how many R groups can be replaced in the rings. Court rejected Sigmapharm’s theory & agreed with BMS. Court said that accepting Sigmapharm’s theory would be in tension with well-established case laws because it results in preferred embodiments being excluded from the scope of the claims. Sigmapharm’s expert agreed that under this interpretation, none of the compounds disclosed in US’208 patent would fall within scope of claim 1. Thus, court found that claim 1 covers apixaban & therefore Sigmapharm’s ANDA infringes dependent claim 13.

With respect to US’945 patent, Sigmapharm argued that BMS failed to prove that its ANDA product contain crystalline apixaban & crystalline apixaban having claimed particle size. But court said that BMS expert, Dr Atwood identified four characteristic crystalline apixaban peaks at 12.3, 12.9, 27.1 & 22.1. In defense, Sigmapharm contended that its expert, Dr. Zaworotko’s XRPD testing revealed no evidence of crystalline apixaban. Court, however, said that Dr. Atwood’s method was more sensitive than Dr. Zaworotko because Dr. Atwood used count times of between 30 and 100 seconds. Sigmapharm non-infringement defense was largly relied on attacking the evidences developed by BMS experts. But court did not find Sigmapharm’s argument persuasive enough to discredit BMS expert. Sigmapharma finally argued that even if some of the apixaban in its ANDA prodcuct is crystallized, there is no “apixaban particle” as required by claims but rather “composite particles consisting of PVP-apixaban bonded together”.  Court, however, said that Sigmapharma has not shown that such composite particles do not contain crystalline apixaban particles. Thus, court concluded that any crystalline apixaban in Sigmapharma’s ANDA product consist of crystalline apixaban particles.

With respect to particle size limitation (D₉₀ less than 89 µm), Sigmapharm argued that BMS has not met its burden of proof because it did not measure any crystalline apixaban particles in tablet. BMS countered that it did not need to measure or calculate precise D₉₀ value because Sigmapharm’s manufacturing process makes it impossible for any crystalline apixaban particles to have D₉₀ greater than 89 µm. Court agreed with BMS & said that there is no general rule requiring to perform actual tests or experiments  on the accused product to prove infringement. Therefore, BMS has proved that Sigmapharm’s ANDA has crystalline apixaban particles with D₉₀ equal or less than 89 µm & thus it infringed US’945 patent.

2. Sunshine’s ANDA:

Sunshine also used similar process where amorphous dispersion was formed using crystalline apixaban & povidone. Court here also said that BMS has proved by preponderance of the evidence that Sunshine’s ANDA product contains crystalline apixaban particles. Dr. Atwood identified crystalline apixaban peaks at 12.3 & 27.1 which are listed in the US’945 patent as characteristics peaks. Sunshine’s expert, Dr. Brittain did not find evidence of  crystalline apixaban in its XRPD testing. Bur court said that Dr. Brittain testing was less sensitive than Dr. Atwood because Dr. Brittain used scan times of 1.75 seconds per step, whereas Dr. Atwood used scan times of upto 1000 seconds per step. With respect to particle size limitation (D₉₀ less than 89 µm), court here also agreed with BMS & said that it has proven that Sunshine’s ANDA meets this limitation. Court said that crystalline apixaban in ANDA product can not exceed 89 µm because apixaban was rapidly dried & used in very small quantity relative to the excipients during manufacturing. Therefore, BMS has proved that Sunshine’s ANDA has crystalline apixaban particles with D₉₀ equal or less than 89 µm & thus it infringes US’945 patent.

3. Unichem’s ANDA:

Unichem manufactured its ANDA product by Fluidized bed process. First dry excipients were fed into fluidized bed granulator. In parallel, starting apixabam API was dissolved in volatile solvents such as methylene chloride & isopropyl alcohol. Then this solution was sprayed onto surface of excipient particles floating in the fluidized bed granulator. Thus, volatile solvents evaporated leaving behind small apixaban particles deposited on excipient particles. After granulation, subsequent steps were undertaken to form tablet. The only limitation Unichem disputed was paticle size limitation.

BMS expert, Dr. Berkland analysed ANDA product using SEM-EDS technique. After observing 68 granules containing thousands of apixaban particles, he determined that all of the particles were 1 µm in size. Therefore, crystalline apixaban in Unichem’s ANDA product had D₉₀ equal or less than 89 µm. Dr. Berkland opined that his conclusions were consistent with Unichem’s manufacturing process which causes evaporation of volatile solvents leaving behind small apixaban particles. Unichem attemped to defeat BMS infringement case but it failed. Court was also not persuaded by Unichem’s affirmative evidence that it’s apixaban API has D₉₀ value between 150 – 1000 µm. Court said that this evidence is based on starting apixaban API, not the apixaban in Unichem’s ANDA product which has different form. Thus, court found that BMS has proven that Unichem’s ANDA product infringes the asserted claims of US’945 patent.

Invalidation:

With respect to invalidation, Defendants put forth various attacks such as improper dependency, lack of enablement, lack of written description and obviousness.  But, court found that Defendants failed to prove that asserted claims are invalid.