API and IP Newsletter
Contents
P-IV filing by generic companies.
We follow ANDA submissions with P-IV filings. One can find everything about P-IV certification in ANDA filings here.
Recently 4 ANDAs were submitted on NCE-1 date for Tafamidis 61 MG capsule. NCE-1 date was in May 2023.
Tafamidis is medication used to delay disease progression in adults with certain forms of transthyretin amyloidosis i.e., stiff heart syndrome.
Patent Data listed in OB for Tafamidis 61 MG capsule is as below.
Exclusivity Data is as below
The date of ANDA filing for Tafamidis could be found here.
We tried to find out who all would be these 4 ANDA filers, it could be only an educated guess.
There are more than 20 DMFs. Any four of them could have filed ANDA.
DMF list is as follows.
Many companies filed patent applications with different polymorphs, processes, salts.
It is interesting to note, the innovator has protected Form-1 till 2035. Hence, all those patent applications holders with different polymorphs and have filed DMFs with different polymorphic forms would be of interest for four ANDA filers.
Following companies imported US innovator samples ie 61 MG capsules
So, there would be high likelihood that 4 ANDA companies could have been among these 8 importers of US innovator samples. Looking at the import dates and sample quantity, could one say Sun, Cipla, DRL and Cadila would be ahead of the rest?
Still, it would be very difficult to guess 4 ANDA filers today. Once Pfizer starts notifying generics then it will be publicly known who all have filed ANDAs on NCE-1 date and would potentially be able to share 180 days exclusivity. We will cover that news too and then we will comment whether our guess is right!
General information
ABIONYX Pharma Successfully Manufactures a Second Batch of Recombinant Human ApoA-I CER-001 Using a New, Innovative and Robust Industrial Bioprocess
Demonstrated success for the industrial biomanufacturing of CER-001, one of the most advanced biomedicines
Confirmation of improved yield and simplification of the biomanufacturing process
Positioning on the biomanufacturing trajectory requiring 3 consecutive batches for Marketing Authorization
News here.
Jardiance approved in EU for the treatment of adults with chronic kidney disease
Key highlights:
Chronic kidney disease (CKD) affects 850 million people worldwide, 47 million in the EU, doubles a person’s risk for hospitalisation and is a leading cause of death.
Jardiance (empagliflozin) is the first SGLT2 inhibitor to demonstrate a statistically. significant reduction in all-cause hospitalisations in people with CKD vs. placebo
The approval in CKD adds to existing indications in type 2 diabetes and heart failure; these interconnected conditions affect over 1 billion people worldwide.
News here
Intellectual Property
Amgen Vs Sandoz
OB listed patents are as below:
Sandoz submitted an ANDA seeking approval from the FDA to market a generic version of apremilast. Celgene, the original plaintiff. In February 2020, Amgen was substituted as plaintiff.
Celgene, the original plaintiff, brought this Hatch-Waxman suit, asserting that Sandoz’s generic product would infringe the ’638 and ’101 patents. After the ’541 patent issued, Celgene asserted infringement of that patent as well.
This write-up is only for `638 patent.
At the district court, Amgen asserted infringement of claims 3 and 6 of `638. In response, Sandoz alleged that those claims were invalid as obvious over U.S. Patent 6,020,358 (the “’358 patent”) and PCT application WO 01/034606 (the “’606 application”).
The ’358 patent is the first U.S. patent describing a racemic mixture containing apremilast, and it claims a genus of phosphodiesterase inhibitors, including a racemic mixture containing apremilast.
The ’358 patent discloses seventeen example compounds that fall within the scope of the claimed genus.
Example 12 of the ’358 patent is a racemic mixture comprised of 50% of the (+) enantiomer of 2-[1-(3-ethoxy-4-methoxyphenyl)-2- methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione and 50% of the (-) enantiomer. The (+) enantiomer is apremilast.
The ’358 patent more generally discloses that racemates can be separated into individual enantiomers.
The ’606 application is directed to a group of phosphodiesterase inhibitors and teaches that the individual enantiomers of racemic mixtures can be separated. Sandoz asserted the ’606 application as reinforcing the teachings disclosed in the ’358 patent.
The district court held that Sandoz had failed to show by clear and convincing evidence that claims 3 and 6 would have been obvious over the ’358 patent and the ’606 application.
In particular, the court found that Sandoz failed to meet the burden of establishing that the ’358 patent and the ’606 application gave a skilled artisan reason or motivation to resolve the Example 12 racemic mixture into its enantiomers, further finding that there was not sufficient evidence to conclude that a skilled artisan would have had reason to believe that the desirable properties of Example 12 derived in whole or in part from the apremilast enantiomer (i.e., the (+) enantiomer).
The court also concluded that Sandoz had not demonstrated that a skilled artisan would have had a reasonable expectation of success in resolving Example 12 into its individual enantiomeric components. Thus matter had reached to the appellate Court, ie CAFC.
Before trial, Sandoz (and Zydus too) had acknowledged that their generic versions of Otezla infringe the asserted claims of U.S. Patent No. 7,427,638 (`638).
Further in this write-up, we will cover CAFC’s opinion about `638 patent and whether the district court had erred while handed down the decision.
Asserted claim 3 of the ’638 patent reads as follows:
3. The pharmaceutical composition of claim 2 [A pharmaceutical composition comprising stereomerically pure (+)-apremilast, or a pharmaceutically acceptable salt, solvate or hydrate, thereof; and a pharmaceutically acceptable carrier, excipient or diluent, wherein said pharmaceutical composition is suitable for parenteral, transdermal, mucosal, nasal, buccal, sublingual, or oral administration to a patient], wherein said pharmaceutical composition is suitable for oral administration to a patient.
Asserted claim 6 of the ’638 patent reads as follows:
6. The pharmaceutical composition of claim 5 [A pharmaceutical composition comprising stereomerically pure (+)-apremilast, or a pharmaceutically acceptable salt, solvate or hydrate, thereof; and a pharmaceutically acceptable carrier, excipient or diluent, wherein said pharmaceutical composition is suitable for parenteral, transdermal, mucosal, nasal, buccal, sublingual, or oral administration to a patient, wherein the amount of stereomerically pure (+)-apremilast is from 1 mg to 1000 mg, wherein the amount of stereomerically pure (+)-apremilast is from 5 mg to 500 mg], wherein the amount of stereomerically pure (+)-apremilast is from 10 mg to 200 mg.
CAFC agreed with Amgen that the district court did not err in finding that claims 3 and 6 of the ’638 patent were not shown to have been obvious by a standard of clear and convincing evidence over the ’358 patent and the ’606 application.
CAFC found no clear error in the court’s holding that Sandoz did not meet its burden of establishing that the prior art gave a skilled artisan reason or motivation to resolve the Example 12 racemic mixture into its enantiomers, to conclude that a skilled artisan would have had reason to believe that the desirable properties of the Example 12 racemic mixture derived in whole or in part from the apremilast isomer, or that a skilled artisan would have had a reasonable expectation of success in resolving the mixture of Example 12.
In making these findings, the court appropriately credited the statements of both Amgen’s and Sandoz’s experts, finding the statements of Amgen’s expert more persuasive.
Included in that testimony was information establishing that resolving a racemic mixture is a difficult process based on trial-and-error experimentation and that using chiral chromatography to resolve the Example 12 racemic mixture into its enantiomers would require a skilled artisan to find an appropriate solvent system for the chiral column, of which there were many possible options at the time the invention was made.
The CAFC further agreed with Amgen, and subsequently affirmed the district court’s finding, that there is no clear error in the district court’s finding of a nexus between the unexpected potency of apremilast and claims 3 and 6 of the ’638 patent
Further, the unexpected properties of a compound necessarily have a nexus to that compound.
First, the district court did not err in determining that, before apremilast, there was a long-felt need for a psoriasis treatment that was suitable for oral administration to a patient without the risks and barriers to adherence that were common with other psoriasis treatments.
In making this finding, the court credited expert testimony establishing that topical treatments, including creams and ointments, had several drawbacks for patients suffering from moderate to severe psoriasis, including messiness, difficulty of application to large areas of affected skin, inability to treat associated psoriatic arthritis, and the tendency for topicals to lose efficacy over time.
The credited expert testimony also established that older oral systemic treatments had their own compliance barriers, including treatments that required lab monitoring before, during, and sometimes after treatment, and for being contraindicated in immunosuppressed patients.
The CAFC also found no clear error with respect to the district court’s findings that others in the field had tried and failed to develop other PDE4 inhibitors, including expert testimony establishing that many PDE4 inhibitors failed to progress in experimentation and trials or were not sufficiently effective at tolerable doses.
The CAFC also found no clear error in the court’s finding that there was industry and regulatory scepticism about the safety of apremilast because of its structural similarity to thalidomide, evidenced by credited expert testimony or that Otezla has achieved commercial success since receiving FDA approval, based on credited expert testimony from Amgen’s economic expert.
In summary, the district court did not err in opining that claims 3 and 6 of the ’638 patent would not have been obvious over the ’358 patent or the ’606 application.
Accordingly, the CAFC affirmed the district court’s holding that Sandoz did not meet its burden to show by clear and convincing evidence that claims 3 and 6 of the ’638 patent would have been obvious over the ’358 patent and the ’606 application.
In this case, in fact, three of Amgen's patents were the subject of the appeal. The appellate court (CAFC) upheld the validity of U.S. Patent No. 7,427,638, which claims pharmaceutical compositions of apremilast, and U.S. Patent No. 7,893,101, which claims a crystalline form of apremilast, but ruled against Amgen on U.S. Patent No. 10,092,541, which claims methods of treating psoriasis with apremilast according to a specific dosing schedule.
We will cover CAFC’s decision about other patents (viz `101 and `541) in subsequent write-ups.
Decision here
