API and IP Newsletter

A brief analysis of imports of Cadila Healthcare and inferences about their development pipeline

Last week we analysed the patent portfolio of Cadila Healthcare. Here, we have tried to dig out some insights from the imports of Cadila Healthcare.

As expected, maximum import is from China, followed by Germany, Italy, and USA. This is no brainer since every Indian Gx company imports from China.

We tried to evaluate the current development pipeline of Cadila Healthcare by analysing its imports. In a very brief analysis of company’s imports during last 4-5 months, we discovered the following:

Intermediate imported by Cadila	Quantity in KGs	FDA Approval date		SIDVIM Comment
1-BROMOCYCLOBUTANE-1-CARBOXYLIC ACID	18	14-Feb-18	Apalutamide intermediate. Must be at late stage of development at Cadila. Relatively higher quantity of intermediate is ordered, could be for kilo lab batches?
TRANS-4-[(TERT-BUTOXYCARBONYL) AMINO] CYCLOHEXANECARBOXYLIC ACID	1		Oclacitinib was approved by the FDA in 2013, Cadila is active in veterinary product?
5 6-DIETHYL-2 3-DIHYDRO-1H-INDEN-2-AMINE HYDROCHLORIDE	0.5	29-Oct-15	Indacaterol intermediate, an inhalation product. Small quantity intermediate imported, may be early stage of development at Cadila. Could be a move in developing skillsets in inhalers?
5-(2R)2-OXIRANYL-8- (PHENYLMETHOXY)-2(1H)-QUINOLINONE	0.5	30-Oct-15	Indacaterol, another intermediate.
(R)-2-((METHOXYCARBONYL) AMINO)-2-PHENYLACETIC ACID	30	19-Mar-20	Velpatasvir intermediate, Sofosbuvir-Velpatasvir, block buster combination, higher quantity of intermediates procurement suggests, Cadila could be at the verge of filing a DMF.
(2S 4S)-2-[5-[1 11-DIHYDRO-2-[(2S 5S)-1-[(2S)-2-[(METHOXYCARBONYL) AMINO]-3-METHYL-1-OXOBUTYL]-5-METHYL-2-PYRROLIDINYL]	97	19-Mar-20	An another Velpatasvir intermediate.
7-CHLORO-1 2 3 4-TETRAHYDRO BENZO [B] AZEPIN-5-ONE	50	19-May-09	Tolvaptan intermediate. Basic development must be complete. DMF could be filed soon?
5-AMINO-3-(TRIFLUOROMETHYL) PICOLINONITRILE	16	14-Feb-18	Apalutamide intermediate. Maybe RMs for kilo lab batches are being procured? At late stage of development at Cadila and DMF could be filed soon?
2-AMINO-6-BROMOPYRIDINE	1		Filgotinib intermediate. The FDA has rejected Gilead's filing for approval of Filgotinib in rheumatoid arthritis. Cadila perhaps would defer development timelines.
ETHYL 2-((TRANS)-4-((TERT-BUTOXYCARBONYL) AMINO) CYCLOHEXYL) ACETATE	6	17-Sep-15	Cariprazine hydrochloride intermediate. Late stage of development at Cadila?
2-(4-AMINOPHENYL) ETHAN-1-OL	0.5	28-Jun-12	Mirabegron intermediate. Very early stage at Cadila API development center?
(3R 4R)-N 4-DIMETHYL-1-(PHENYLMETHYL)-3- PIPERIDINEAMINE DIHYDROCHLORIDE	29	30-May-18	Tofacitinib intermediate. DMF filed by the Cadila. Higher quantity of intermediate import suggests Cadila could be procuring to support ANDA filing?
(1S)-4 5-DIMETHOXY-1-(METHYLAMINOMETHYL)- BENZOCYCLOBUTANE HYDROCHLORIDE	60	15-Apr-15	Ivabradine intermediate. DMF filed by Cadila. Pilot plant batch quantity is being procured. Maybe Cadila is intending to file ANDA and hence producing own API for ANDA filing?

This is very brief analysis of just last 4-5 months import as described earlier. More details could be found out by analysing more data. We would provide such insights for other companies in near future. Please find some additional information in the attached file.

Insights of Cadila Development

General information

Understanding the Importance of Crystallization Processes

Every API brings its challenges to crystallization and scale-up. Although there are general steps to understanding the crystallization process—the solubility, the metastability, the chosen process solvent, and the critical process parameters—these will not be the same for all APIs. Innovative and bespoke crystallization development goes into establishing a good, robust process, and the lack of a one-size-fits-all solution means the experience of process scientists in this field is invaluable to identify the clues that screening gives towards a robust, commercial solution. (Read more)

Regulatory Compliance Trends

In the pharmaceutical sector specifically, the global regulatory affairs outsourcing market is expected to be worth $14.3 billion by 2026, a CAGR of 12%.1 Meanwhile, the whole medical device outsourcing market is expected to be worth over €230 billion by 2027. There is clearly a growing trend for quality, compliance, and regulatory outsourcing, and it is likely to be accelerated by the healthcare crisis. (Read more)

Intellectual Property

Everolimus USA

Everolimus has become generic in December 2019. This case is about the IPR decision.

IPR decision: 05-Oct-20

AIA Review #	Filing Date	Petitioner	Patent	Respondent	Final Written Decision
IPR2016-01479	22-Jul-2016	Par Pharmaceutical, Inc*.	9,006,224	Novartis AG	Challenged claims patentable

US 9,006,224 (Novartis AG; Exp: 07/01/2028)

Claim: A method for treating pancreatic neuroendocrine tumors, comprising administering to a human subject in need thereof a therapeutically effective amount of 40-O-(2-hydroxyethyl)-rapamycin (Everolimus) as a monotherapy and wherein the tumors are advanced tumors after failure of cytotoxic chemotherapy.

1. *This proceeding as initially filed, named Par Pharmaceutical, Inc. as the sole Petitioner. Argentum Pharmaceutical LLC joined later.

2. Then, West-Ward Pharmaceuticals joined

3. Subsequently, Par and West-Ward separately requested termination of their participation in the proceeding pursuant to settlement.

4. Argentum Pharmaceutical LLC is the sole remaining Petitioner.

There were many references cited which were evaluated during the proceeding.

1. Oberg et. al. disclosed the algorithm for the therapy of neuroendocrine, and Rapamycin was identified (individualised) for the treatment.

2. Baulay et. al. taught Everolimus is effective in pancreatic tumour model in rats.

3. O’Donnell described the P-I study of Everolimus and indicated plausible weekly dose of the drug.

4. Duran, disclosed trials of Temsirolimus which is pharmacologically different than Everolimus or Rapamycin.

In IPR decision, Board disagreed to the Petitioner for their request to revoke the patent, said, all these references do not hint at a reasonable expectation of success to the skilled person, especially for treating advance PNETs after failure of cytotoxic chemotherapy. Patent was maintained.

Generics must launch with the skinny label though. Objective of this news is not to study financial impact of carve-out label, but certainly, some patient population would be covered by the patented indication and Novartis would be able to maintain the market share to that extent.

News here.

IPR decision here.

Disclaimer: Sidvim LifeSciences Private Ltd has taken due care and caution in developing this document. Since the data used for analysis in this document is based on the information available in the public domain, its adequacy or accuracy or completeness cannot be guaranteed. This document is for information only and Sidvim is not responsible for losses that may or may not arise due to any decisions made based on the same. No part of the document shall constitute or be represented as a legal opinion of any kind or nature. No warranties or guarantees, expressed or implied, are included in or intended by the document, except that it has been prepared in accordance with the current generally accepted practices and standards consistent with the level of care and skill exercised under similar circumstances by professional consultants or firms that perform the same or similar services.

Sidvim LifeSciences Private Limited