API and IP Newsletter
Contents
DMFs filed by Lupin Ltd
We analyse DMFs filed by generic companies. This document covers only part of the analysis, of DMFs filed by Lupin, confining to only 4-5 DMFs filed in the recent past.
Probable conclusions:
Lupin is perhaps concentrating DMF filing efforts to ensure NCE-1 dossier filings.
Development of APIs must have started much before FDA approvals or immediately after FDA approvals.
All dosage forms are targeted including inhalers. Lupin could have their own technology for the devices.
General information
Horizon Therapeutics Plc filed a lawsuit alleging that Apotex Inc.’s copy of Pennsaid 2%
Horizon Therapeutics Plc filed a lawsuit alleging that Apotex Inc.’s copy of Pennsaid 2% infringes a patent for the topical osteoarthritis treatment because Apotex “has begun or is imminently about to begin” selling it despite a Teva unit’s 180 days of regulatory exclusivity for its generic version.
The Federal Circuit in October 2019 upheld the patent’s validity, rejecting arguments by Teva’s Actavis that it didn’t cover a new idea. The patent, which expires in October 2027, covers a gel formulation that includes diclofenac sodium and is used for topical treatment of pain, such as that from osteoarthritis. ...
News here.
Ukraine: Cancellation of marketing authorizations for pharmaceuticals manufactured in Russia or Belarus or held by companies affiliated or otherwise related to those with manufacturing facilities in Russia or Belarus
The Parliament of Ukraine adopted draft law No. 7313 ("Draft Law") aiming to prevent the turnover of pharmaceuticals manufactured in Russia or Belarus or marketed by marketing authorization holders affiliated or otherwise related to companies with pharmaceutical manufacturing in these countries. To become effective, the Draft Law would need to be signed by the president of Ukraine and published in the official gazette. The Draft Law will come into force on the next day after it is published and will remain effective for three months after the termination or cancellation of martial law.
The pharmaceutical industry in Ukraine is deeply concerned about the absence of straightforward criteria in the Draft Law to determine which specific marketing authorizations would be suspended or cancelled.
News here.
Intellectual Property
Delaware Court ruled against Astellas Pharma and Gilead (innovator) in a patent case related to Regadenoson. Hospira succeeded.
Regadenoson, sold under the brand name Lexiscan. Regadenoson is used to test the heart for coronary artery disease. It is used in patients who cannot exercise for their stress test.
According to IQVIA sales data for the 12-month period ending November 2021, the Lexiscan Injection market achieved annual sales of approximately $659.9 million.
Innovator asserted three patents. They allege that Hospira's submission of its ANDA to the FDA constitutes infringement of claim 1 of US 8,106,183 (the #183 patent) and claim 6 of US RE47,301 (the #301 patent)
Hospira denied.
Matter was before Delaware Court.
Claim 1 of the #183 patent reads: "A monohydrate of Regadenoson, which monohydrate is in a crystalline form, ( ie Form A)
Claim 6 of the #301 patent states: A pharmaceutical composition of crystalline monohydrate form of Regadenoson (Form A)
XRPD analysis of Form A regadenoson showed peaks near, among other points, 5.6, 9.1, 1 I.I, 13.1, 14.4, and 16.8° 2-theta.
It was undisputed that the most intense peak in Form A's XRPD diffractogram occurs at 5.6° 2-theta, as shown in Figure 3 of the #183 patent
API supplier of Hospira was Curia, who is offering Form G.
Two samples of Form G regadenoson taken from batch 856, one in late 2015/early 2016 and one in 2020, Innovator relied solely on tests on two samples from the 856 batch to show that Curia's Form G API will more likely than not contain Form A.
The first test showed a single XRPD peak at about 5.6° 2-theta. When the samples from the 856 batch were tested one month and then again two months after the first test, "no peak was detected between five and six 2-Theta."
It was accepted that Form A is the only known monohydrate crystalline form of regadenoson and is the most stable of the known regadenoson crystalline form.
Hospira and Curia did not want Form A to be used in or result from Curia's manufacture of Form G. Hospira and Curia knew that Innovator owned patents that covered Form A, and Hospira and Curia wanted to avoid infringement of those patents.
Innovators alleged that Curia disclosed in its original DMF that Curia considered Form A as an impurity/intermediate in its process.
Hospira and Curia nonetheless had reason to be concerned at the time Hospira filed its ANDA that Form A could result from the exposure of crude and Forms F and G regadenoson to water in Curia's manufacturing process. Curia had conducted and brought to Hospira' s attention XRPD test results that suggested the presence of Form A in samples of crude and Forms F and G regadenoson taken from Curia's manufacturing process in 2016.
As a result of those concerns, Curia amended its DMF in 2021 to optimize its manufacturing process to limit the presence of water in the process and tightened its specifications for the identification of Form G by XRPD.
Specifically, Curia amended the specifications and stability sections of its DMF to explicitly require the identification of the final Form G product by an XRPD analysis in which the sample pattern conforms to the Regadenoson anhydrous Form G reference pattern, designated prominent peaks are present, and no peaks are observed for other solid forms.
Curia also amended its corresponding analytical procedures relating to the XRPD testing.
The court noted the following
As a result of these amendments, Curia's existing DMF specifications rule out the observation of any other solid forms, including Form A regadenoson, in Curia's final product.
Moreover, the analytical method used for the amended DMF and ANDA specifications requires that no peaks are observed in the ranges of 3-7° and 9.5-14° 2-theta.
And although identification methods typically do not assess low intensity peaks, Curia's current method expressly requires evaluation of sample patterns for any peaks above the noise level in the two regions of interest.
Therefore, any peak at or near 5.6° 2-theta of any intensity above noise would trigger a failed specification, and the batch would be rejected and ultimately disposed of. Such a specification failure would also mean that Hospira wouldn't be able to use that batch.
The 2021 batch records also require more than 20 additional in process checks throughout the crude, Form F, and Form G stages to ensure that the water specification for ethanol is below the specified level (1000 ppm) at all stages of the process and each time it is used.
Because Hospira's ANDA incorporates Curia's DMF, and Curia has no Form G remaining that was manufactured according to the original pre-2021 process available for sale to Hospira, going forward, the ANDA product that Hospira will market will be manufactured using Form G prepared by Curia according to Curia's amended process and in a manner consistent with Curia's extant XRPD specifications, batch records.
Innovator did not adduce at trial evidence of synchrotron testing of the 2021 batch samples, even though synchrotron tests yield the lowest potential limit of detection for Form A regadenoson and therefore would have provided the best evidence for them to prove that Form A exists in Curia's API, but that it's not observed in standard XRPD testing. Nor did innovator employed any other alternatives that would have enabled them to prove the presence of Form A in Curia's Form G in trace amounts.
As an initial matter, all the pre-2021 testing results cited by the Innovator are based solely on the identification of a single XRPD peak at around 5 .6° 2-theta.
The Court found, however, that a single XRPD peak is insufficient to identify Form A by a preponderance of the evidence since four known forms of regadenoson-Forms A, B, D, and E have a peak within the margin of error of 5.6° 2-theta, and as yet undiscovered forms of regadenoson could also have a peak within the margin of error of 5.6° 2-theta.
It is undisputed, however, that Form A's most prominent peak occurs at 5.6° 2-theta and that Form G does not have such a peak. Accordingly, it makes sense that the employees who reviewed the test results would conclude that the tests showed that Form A could be present in the tested Form G samples.
The Court agreed with Innovators that the three tests that failed to detect Form A peaks could have been false negatives (because they were taken from regions where conversion had not yet occurred in the 856 batch). But it is also the case that the two tests that detected a Form A peak could have been false positives (because they were exposed to atmospheric moisture after being removed from the batch). Innovator, however, bear the burden of proof here.
The Court further said, the test results for the 856 batch samples do not establish by a preponderance of the evidence that Curia's Form G API will likely convert to or contain Form A.
On the contrary, the Court found Dr. Steed's testimony to be logical and credible. And based on that testimony and the inconsistent results from the 856 tests, the Court found that, even were a single peak sufficient to identify Form A, any Form A in the two positive 856 samples likely resulted from airborne water exposure during their sampling, storage, transport, and/or testing.
Innovator argued that Hospira induced Curia's infringement of claim 1 of the #183 patent because Form A will be made at the crude and Form F stages of Curia's manufacturing process. But the Court said that innovator failed to establish by a preponderance of the evidence that the crude or Form F regadenoson in Curia's manufacturing process contains or likely will contain Form A. The Court opined in favour of Hospira.
Decision here
