API and IP Newsletter

 Contents

• ANDA approvals in June 2023

• General information

• Verrica's drug gets US nod as first treatment for a type of skin infection

• Invivoscribe Gets FDA Approval for LeukoStrat CDx for Daiichi Sankyo Leukemia Drug

• Intellectual Property

• Exelixis, Inc. v. MSN Labs

ANDA approvals in June 2023

We follow ANDA approvals of Indian companies. We briefly check who are the competitors, what could be business potential for the company, we estimate complexities which could have been involved in filing the ANDAs.

In the month of June 2023, total 97 ANDAs were approved and out of which 13 were Tentative Approvals. 

Amneal and Eugia Pharma toped the list with 4 ANDA approvals each; Alembic and Sun are at 3 each. 

Some of our observations are as below.

Drug Name	Company	Sidvim comments
OLMESARTAN MEDOXOMIL AND HYDROCHLOROTHIAZIDE ANDA  #204801	MACLEODS PHARMS LTD	This is hydrochlorothiazide; olmesartan medoxomil 12.5 MG;20 MG: 12.5 MG; 40 MG: 25 MG; 40 MG. There are several Generic already in market. Recent sales in US is not available in public domain but even after it became generic, about 3 years ago, it was over USD 1 bn product.
NADOLOL                               ANDA  #211763	ALEMBIC	Nadolol is a medication used to treat angina and hypertension. This is 20, 40 and 60 MG tablets. Very old drug. Too many ANDA filers. Nadolol Tablets USP, 20 mg, 40 mg, and 80 mg Tablets had annual sales of approximately USD 100 million in the US. API suppliers would be limited there are only four active DMFs. API sourcing could have been a challenge. This is reasonably costly API, for regulated market it is priced above USD 800-1000/Kg. This appears to be relatively simple chemistry at the first glance!
BENDAMUSTINE HYDROCHLORIDE                  ANDA  #214739	EUGIA PHARMA	This approval is for 100MG/4ML(25MG/ML) infusion. There are many other ANDA filers. Bendamustine hydrochloride injection is an alkylating drug approved by FDA for treatment of patients with Chronic lymphocytic leukemia (CLL) and Indolent B-cell non-Hodgkin lymphoma (NHL). Bendamustine hydrochloride injection generated sales of $133 million three years ago.
TADALAFIL                             ANDA  #212515	ZYDUS PHARMS	This is 20 MG tablet. The Adcirca brand and generic had US sales of approximately $490 million. Tadalafil is generally indicated in the treatment of impotency, erectile dysfunction and enlarged prostrate, among others. There are too many generic options available in US market. Zydus would be one among many.
CYCLOPHOSPHAMIDE             NDA   #210852	DR REDDYS	This is IV, 500MG/ML (500MG/ML),  1GM/2ML (500MG/ML) and 2GM/4ML (500MG/ML).  Cyclophosphamide for Injection USP, 500 mg, 1 g and 2 g had annual U.S. generic sales of approximately $332 million according to IQVIA two years ago. There are several generics in US market.  However, this is Type 5 - New Formulation Submission. Kindly note, once a new dosage form has been approved for an active ingredient, subsequent applications for the same dosage form must submit under Type-5. More details about dossier submission types at USFDA could be found here.  Ingenus Pharmaceuticals LLC had an earlier approval of new dosage form of an active ingredient.  All the formulations of Cyclophosphamide known prior to Ingenus approval and described in literature required reconstitution with a diluent liquid which obviously would have decreased the ease of administration. Moreover the reconstituted and diluted solutions can be stored only for a fixed period.  After Ingenus Pharmaceuticals LLC, DRL filed dossiers with new formulations and hence dossier submission classified as Type 5.  Technically this is NDA and not ANDA. This differentiates DRL from rest of the lot.  DRL must have circumvented granted US patent US10993952B2 before the launch.

General information

Verrica's drug gets US nod as first treatment for a type of skin infection

The green light for Verrica's drug, Ycanth, makes it the first approved treatment for viral skin disease molluscum contagiosum in the United States. 

News here.

Invivoscribe Gets FDA Approval for LeukoStrat CDx for Daiichi Sankyo Leukemia Drug

Invivoscribe announced on Friday that its LeukoStrat CDx FLT3 Mutation Assay has received approval from the US Food and Drug Administration to select patients with FLT3-ITD positive acute myeloid leukemia who may be eligible for treatment with Daiichi Sankyo's Vanflyta (quizartinib). 

News here

Intellectual Property 

Exelixis, Inc. v. MSN Labs 

We covered Cabozantib case couple of months ago, where MSN obtained mixed verdict. In the earlier draft, we discussed about compound patent, in this write-up let us discuss polymorph patent. US 8877776.

Claim 1 of the '776 patent states:

1. N-(4-([6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (L)-malate salt (Cabozantinib malate), wherein said salt is in crystalline Form N-2 and said Form N-2 is characterized by at least one of the following:

(i) solid state 13C NMR spectrum with four or more peaks selected from 23.0, 25.9, 38.0, 41.7, 69.7, 102.0, 122.5, 177.3, 179.3, 180.0, and 180.3, ±0.2 ppm;

(ii) a powder x-ray diffraction pattern (CuKa X=1.5418 A) comprising 20 values at 20.9±0.2 °20 and 21.9±0.2 °20, and two or more 20 values selected from: 6.4±0.2 °20, 9.1±0.2 °20, 12.0±0.2 °20, 12.8±0.2, 13.7±0.2, 17.1±0.2, 22.6±0.2, 23.7±0.2, wherein measurement of the crystalline form is at room temperature; and/or

(iii) an x-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern shown in FIG. 8. (Figure 8 could be seen on page 11 here)

1. Now, for infringement of claim 1 of the '776 patent, Exelixis had to prove that Form N-2 will be detected in MSN's proposed ANDA product according to 13C NMR test criteria (limitation l(i)) and/or XRPD test criteria (limitations l(ii) or l(iii)). 

2. Kindly note, MSN had developed API which is Form S, and had non-infringing argument wrt form N-2.

3. MSN contends that its tablets will include only Form S of cabozantinib, where MSN formulated Form S as a design around for Form N-2. 

4. Exelixis disagreed, argued that Form S is unstable and, over time, will convert to Form N-2, thus causing infringement. 

5. The parties dispute whether Exelixis has proven by a preponderance of the evidence that MSN's tablets, which will be manufactured using Form S as the API, will infringe limitation 1 (i) of claim 1. 

6. At trial, Exelixis provided no direct evidence of 13C NMR or XRPD test results detecting Form N-2 in MSN's tablets. 

7. Exelixis’ expert Dr. Munson did not directly detect Form N-2 in MSN's Tablets. Instead, Exelixis presented evidence that Dr. Munson detected Form N-2 in MSN's API through 13C NMR testing. 

8. Dr. Munson's testing of MSN's API did not detect Form N-2 in MSN's three-year-old as-provided samples, however, Dr. Munson only detected Form N-2 in MSN's API after subjecting the test samples to “accelerated conditions.”

9. Hence the court found that MSN did not infringe the ’776 patent.  The court disagreed that Exelixis had met its burden to show infringement. The Court said. Exelixis’s expert tested MSN’s expired, three-year-old samples and did not detect From N-2. Further, Exelixis detected Form N-2 only after subjecting MSN’s API and finished dosage form to accelerated conditions. 

10. The court explained that Exelixis failed to demonstrate that the accelerated conditions were representative of MSN’s manufacture or storage conditions.

Thus, MSN obtained favourable decision on polymorph claims. 

Decision here