API and IP Newsletter

 Contents

• ANDA approved in the month of January 2023

• General information

• AstraZeneca progresses application for $360m Ireland manufacturing site

• Five potential EU regulatory changes impacting the life sciences industry in 2023

• Intellectual Property

• Cabozantinib (Cabometyx®)- Exelixis Vs MSN in The United States District Court for the District of Delaware

ANDA approved in the month of January 2023

We follow ANDA approvals of Indian companies every month. 

In January there are total 91 approvals and out of which about 20 are tentative approvals. 

Lupin received 4 approvals, Aurobindo and MSN received 3 approvals. 

Some of our observations are as below. 

Active Ingredients	Company	SIDVIM Comments
FESOTERODINE FUMARATE	ALEMBIC PHARMS	This is for 4 MG ER Tablet, Day-1 launch was on 03 January 2023. Five other companies received approval. As per IQVIA, fesoterodine fumarate had an estimated annual market size of $177 million as of September 2022
LEVOMILNACIPRAN HYDROCHLORIDE	AUROBINDO PHARMA LTD	These are 20 MG, 40 MG, 80 MG and 120 MG ER capsules. Levomilnacipran ER capsule sale is about 85 mio in USA. It is a small product. Zydus also received approval.
BRIVARACETAM	AUROBINDO PHARMA LTD	This approval is for 50 mg and 100 Mg tablets. Brivaracetam tablets USP 10 mg, 25 mg, 50 mg, 75 mg, and 100 mg had annual sales of $412 million in US according to IQVIA. Zydus received shared 180 exclusivity earlier.
NORETHINDRONE	AUROBINDO PHARMA	This is 0.35 MG tablet. There are few other competitors. There are about USD 360 mio product in US.
PRASUGREL	LUPIN LTD	This approval is for 5 and 10 MG tablets. There are several Gx approvals earlier.  Prasugrel Tablets USP, 5 mg and 10 mg, (RLD Effient) had estimated annual sales of USD 18 million in US. (IQVIA MAT September 2022)

General information

AstraZeneca progresses application for $360m Ireland manufacturing site

AstraZeneca (AZ) has progressed its application for its $360m ‘next-generation’ active pharmaceutical ingredient manufacturing (API) facility in Ireland, with a final decision on the project due later this month.

Originally announced by the company in September 2021, the facility will be built at the Alexion Campus in College Park in Dublin and produce APIs – the substances in drugs that are responsible for the beneficial health effects experienced by patients – to meet its growing drug pipeline.

News here.

Five potential EU regulatory changes impacting the life sciences industry in 2023

Eight years following its adoption in 2014, the Clinical Trials Regulation 536/2014 (CTR) entered into application on 31 January 2022. The regulation replaces the Clinical Trials Directive (CTD) and the related national implementing legislation of individual EU member states over a transitional period. The CTR introduces a single set of rules for many aspects of clinical trials conducted in the EU rather than the largely national, and often inconsistent, rules created by the CTD. 

1. Until 30 January 2023, sponsors had the option to submit new applications for approval of clinical trials in accordance with either the CTD or the CTR

2. From 31 January 2023, all new applications for approval of clinical trials must be submitted in accordance with the CTR. Authorisation of the clinical trial, may, however, be obtained later.

3. From 31 January 2025, new and ongoing clinical trials in the EU must be conducted in compliance with the CTR.

News here.

Intellectual Property 

Cabozantinib (Cabometyx®)- Exelixis Vs MSN in The United States District Court for the District of Delaware 

This litigation is about two patents listed in OB, viz '473 and '776 for Cabometyx®. 

The '473 patent discloses compounds including cabozantinib that are tyrosine kinase inhibitors (TKIs).

The '776 patent is directed to a particular crystalline form of cabozantinib (L)-malate called Form N-2. 

This write-up is confined to the `473 patent. 

MSN submitted Abbreviated New Drug Application ("ANDA") for cabozantinib tablets. MSN filed Paragraph IV certifications" for both the '776 and '473 patents. 

Exelixis received notice of MSN's Paragraph IV certifications and initiated the present lawsuit. 

In structural obviousness type of arguments, the Court decides whether a new chemical compound would have been prima facie obvious over prior art. 

First, the court would determine whether a chemist of ordinary skill (POSA) would have selected the asserted prior art compounds as lead compounds, or starting points, for further development efforts.

What is a lead compound according to the Court? 

A lead compound is a compound in the prior art that would be most promising to modify to improve upon its activity and obtain a compound with better activity. In determining whether a chemist would have selected a prior art compound as a lead, the analysis is guided by evidence of the compound's pertinent properties, including positive attributes such as activity and potency and adverse effects such as toxicity. 

Second, the court would determine whether the prior art would have supplied POSA with a reason or motivation to modify a lead compound to make the claimed compound with a reasonable expectation of success.

 

The '473 patent requires the chemical structure of cabozantinib or a pharmaceutically acceptable salt thereof. Claim states: 

A compound represented by the structure: 

or a pharmaceutically acceptable salt thereof.

1. Kirin (WO1997017329A1) is prior art to the '473 patent. A POSA would have considered Kirin when pursuing TKIs that inhibit c-Met. 

2. Kirin discloses 333 "preferred compounds" that inhibit c-Met. 

3. Kirin's preferred compound 5 ("Example 5") is a malonamide. 

4. Exelixis arguments are as below:

1. A POSA reviewing Kirin would have recognized a general preference for the use of thioureas and ureas as c-Met inhibitors. 

2. Considering Kirin, a POSA would not have categorically deprioritized all its exemplary thioureas when identifying lead compounds. 

3. A POSA would not have been motivated to modify Example 5 to include a cyclopropyl group because this modification would have caused the POSA to have concerns regarding toxicity. 

4. A POSA would not have been motivated to modify Example 5 to include a cyclopropyl group because this modification would have caused them to have concerns regarding a reduction in potency. 

5. A POSA would not have been motivated to modify Example 5 to pursue an irreversible inhibitor. 

6. A POSA would not have had a reasonable expectation that modifying Example 5 to include a cyclopropyl group would be successful due to the unpredictability in making this modification. 

5. MSN argued 

1. claim 5 of the '473 patent is invalid as obvious based on a lead compound analysis. 

2. a POSA would have been motivated to inhibit c-Met to treat cancer and, with that motivation, would have selected Kirin Example 5 as a lead compound for further development.

3. at the time of the invention, a POSA would have known that inhibiting tyrosine kinases could treat a variety of cancers and that many pharmaceutical companies were developing TKIs to treat cancer. 

4. c-Met is a tyrosine kinase that researchers would have been motivated to research. With that motivation, MSN explained that, at the time of the invention, Kirin was the only prior art reference that disclosed specific exemplified small-molecule c-Met inhibiting compounds.

5. Kirin disclosed 333 "preferred compounds" that inhibit c-Met. Thus, MSN argued, following the motivation to pursue a c-Met inhibitor to treat cancer, a POSA would have chosen a lead compound from the Kirin Publication. 

6. Exelixis disagreed, argued that, at the time of the invention, a POSA would have been aware that researchers had identified many different types of targeted therapies to treat cancer of which tyrosine kinase inhibition represented just one approach. 

7. Further, Dr. George (The exert of innovator) explained that, even within the class of TKIs, there were more than 20 different kinase targets other than c-Met that were under evaluation. 

8. Based on this, Dr. George testified that there would have been no motivation to pursue a c-Met inhibitor compared with other better-known targets at the time. 

9. However, MSN argued that, considering Kirin, a POSA would have started with the exemplary compounds with the highest potency, then narrowed them down based on toxicity, bioavailability, and potential for irreversible inhibition. 

10. The expert Dr. Lepore testified that a POSA would have known that malonamides, unlike the ureas, have the potential for irreversible inhibition.

11. There are two closest examples in Kirin. Between Example 269 and Example 5, MSN argued that a POSA would have deprioritized Example 269 based on the Lipinski criteria here. 

12. The Court did not agree with MSN, found that MSN has not proven by clear and convincing evidence that a POSA would have been motivated to modify Example 5 to form cabozantinib. While MSN argued that this modification would improve stability, the Court did not find that MSN had proven that this improvement could justify the substantial risks outlined in the experts’ testimony. 

So, the Court opined in favor of Exelixis, stated MSN failed to prove by clear and convincing evidence that ‘473 patent is invalid as obvious 

Decision here.