API and IP Newsletter

 

Contents

• DMFs filed by Dr. Reddys Laboratories Limited.

• General information

• Jitendra Singh calls for equal stake participation by industry to sustain start-ups

• Sun Pharma presents Phase 3 data for WINLEVI (clascoterone) cream 1%

• Intellectual Property

• Pirfenidone (Esbriet), opinion of Delaware Court

DMFs filed by Dr. Reddy’s Laboratories Limited. 

Dr. Reddy’s laboratories Limited (DRL) is not filing too many DMFs, on the contrary they are very selective in DMF filings. One can read DRL’s strategy by analysing their DMFs. 

DRL files DMFs for complex molecules, files DMFs which could allow ANDA filers an edge over others. Lenvatinib solvate and now form C of Lenvatinib, enalaprilat are some of the glaring examples.  

DMF	Sidvim comments
LOSARTAN POTASSIUM (FORM-1)	DRL had earlier filed Form I DMF in 2007. This could be new process for Form I
ERIBULIN MESYLATE	Very complex molecule, there are three fractions to be combined to manufacture eribulin. DRL had earlier filed DMF for one of the fractions. DRL seems to be first Indian company to file DMF for eribulin.
Enalaprilat USP	Enalaprilat is the active metabolite of enalapril. DRL drug product was discontinued earlier as per OB. Now Hikma and Hospira are in market, perhaps DRL will file ANDA again.
SEMAGLUTIDE	A complex peptide. DRL is first Indian company to file DMF. As per public domain information DRL manufactured it by 100% synthetic route. Zydus and Sun filed soon after DRL.  Teva and Novo's  patent settlement will allow the generic version of Teva in December 2023. DRL could launch after Teva.
LENVATINIB MESYLATE (FORM-C)	Second Lenvatinib DMF filed by DRL, first was filed in 2018, it was MIBK solvate. First DMF must have been filed for those ANDA filers who were interested in circumvention of OB listed patent of Form C  ie US 7,612,208 expiring in 2026. This Form C Lenvatinib DMF must be for all filers in the second wave.

General information

Jitendra Singh calls for equal stake participation by industry to sustain start-ups

The Union Minister was speaking at the ceremony to sign an Agreement between the Technology Development Board (TDB) of the Ministry of Science and Technology and M/s Sapigen Biologix Private Limited, Hyderabad helmed by Dr Krishna Ella of Bharat Biotech Ltd for the development and commercialization of two novel vaccines – “Intranasal Covid-19 Vaccine and RTS, S Malaria Vaccine”.

There will be an equal stake for both sides with each side contributing Rs 200 crore respectively for ensuring sustainable startups.

News here.

Sun Pharma presents Phase 3 data for WINLEVI (clascoterone) cream 1%

Sun Pharmaceuticals Industries announced that the Company's wholly owned U.S. subsidiary presented data from two pivotal Phase 3 clinical trials of WINLEVI (clascoterone) cream 1% for the topical treatment of acne vulgaris (acne). The results, which showed favorable safety and efficacy data in patients 12 years of age and older with acne, were reported today in a poster podium presentation at the American Academy of Dermatology (AAD) 2022 Annual Meeting in Boston, Massachusetts.

News here.

Intellectual Property 

Pirfenidone (Esbriet), opinion of Delaware Court 

This action arises from Sandoz  filing ANDA seeking to market 267 mg pirfenidone capsules and 267 mg and 801 mg pirfenidone tablets prior to the expiration of Genentech' patents.

Pirfenidone is a drug used to treat idiopathic pulmonary fibrosis ("IPF"). There is no cure for IPF and patients living with the disease face an average survival of two to five years.

There are currently two drugs that have been approved by the FDA for the treatment of lPF, pirfenidone and nintedanib.

Pirfenidone was first studied as an "investigational new drug" in 1973.  On 5 March 2004, the FDA granted pirfenidone U.S. "orphan drug" status for the treatment of patients with IPF. Present sale of Pirfenidone in US is about USD 700-800 mio. (Here) 

1. There are two sets of patents in Orange Book which are asserted by Genetech, “the Liver Function Test (LFT) patents" are directed toward methods "for administering pirfenidone to a patient that has exhibited abnormal biomarkers of liver function in response to pirfenidone administration and ("the Drug-Drug Interaction (DDI) patents" are directed toward "methods involving avoiding adverse drug interactions with fluvoxamine and pirfenidone or other moderate to strong inhibitors of CYP enzymes. 

2. The Asserted Claims of the LFT patents disclose methods for responding to a Grade 2 abnormality in liver function biomarkers (specifically, ALT and AST) in a patient taking pirfenidone to treat IPF by doing one of the following: (1) temporarily reducing the dose of pirfenidone and then returning to the full dose (2400 mg/day or 2403 mg/day), (2) maintaining the full dose of pirfenidone (2400 mg/day or 2403 mg/day), (3) reducing the dose of pirfenidone to 1600 mg/ day or 1602 mg/ day, ( 4) discontinuing pirfenidone "for about a week" and then returning to the full dose, (5) discontinuing pirfenidone "for about a week" and then returning to a dose of "at least 1600 mg/day," or (6) reducing the dose ofpirfenidone to "at least 1600 mg/day or 1602 mg/day." 

3. Pirfenidone, unlike nintedanib is highly susceptible to drug-drug interaction with CYP1A2 inhibitors. InterMune first discovered this in its 2008 study, finding the blood concentrations of Pirfenidone on average went up six times, sixfold, in patients that were on in subjects that were on fluvoxamine. So that's a very substantial drug-drug interaction, particularly in the context of Pirfenidone.

4. The parties agree that Sandoz's label recommends using pirfenidone for the treatment of IPF and includes treatment instructions for patients exhibiting Grade 2 elevations in ALT and/or AST. Indication and Grade 2 elevations, however, are only two of the three limitations of each Asserted Claim. Each claim also requires a dose modification, and the parties disagree over whether Sandoz's label encourages, recommends, or promotes any of the dose modifications disclosed in the Asserted Claims. 

Infringement and validity

5. Sandoz's label merely provides physicians with multiple dose modification options, some covered by the Asserted Patents and some not, and leaves it to the physician's clinical judgment to determine how to modify the patient's dosage. Because Genentech have not shown that Sandoz's label evinces a specific intent to induce infringement of the LFT patents and Genentech presented no other evidence of Sandoz's specific intent, Genentech have not met their burden of proving infringement with respect to the LFT patents. 

6. The court also agreed with Sandoz that the Asserted Claims of the LFT patents are invalid for obviousness over the Azuma Article, the Pirespa Label, and standard practice generally disclosed in the prior art.

DDI patents

7. Sandoz argued, "Each of these claims is invalid for obviousness in view of the combination of the Pirespa Label, 2008 Pirfenidone Report, the Luvox [fluvoxamine] Label, and either the '644 Publication (prior art) or the FDA DDI Guidance." 

8. Specifically, Sandoz argues: (1) a POSA would have expected a drug-drug interaction between pirfenidone and fluvoxamine, (2) Because a POSA would have expected a clinically significant drug-drug interaction between pirfenidone and fluvoxamine, any POSA who wanted to administer pirfenidone to an IPF patient who was also receiving fluvoxamine would have employed standard strategies for avoiding drug-drug interactions, and (3) Routine testing, as recommended by the FDA, would have confirmed the drug[-]drug interaction between pirfenidone and fluvoxarnine.

9. What was believed at the time about pirfenidone's potential for drug-drug interactions is reflected in the Pirespa Label (pirfenidone label): It is estimated that pirfenidone is insusceptible to CYP inhibition by other drugs since multiple CYP molecules are involved in metabolism reaction.

10. The 2008 Pirfenidone Report also taught that pirfenidone was not susceptible to drug-drug interactions. "Pirfenidone is unlikely to have pharmacokinetic interactions with other drugs," because, in part, "Pirfenidone is metabolized not by a particular CYP isoform but by multiple isoforms (CYP1A2, 2C9, 2C19, 2D6, and 2El) and is therefore unlikely to be affected by CYP inhibition by concomitant drugs .... " 

11. The Court found that the language in the Pirespa Label and the 2008 Pirfenidone Report expressly teaching pirfenidone is not susceptible to CYP inhibition by concomitant drugs belies Sandoz' s argument 

12. In view of ( 1) the express teachings-away of the Pirespa Label and the 2008 Pirfenidone Report, (2) the fact that fluvoxamine was known to inhibit only between three and four of the five enzymes responsible for the metabolism of pirfenidone, (3) the lack of an understanding at the time that any one of the five identified CYP enzymes was primarily responsible for the metabolism of pirfenidone, and (4) the general understanding at the time that drug-drug interactions involving drugs metabolized via multiple enzymes were the exception rather than the expectation, the Court found that Sandoz has not proven by clear and convincing evidence that a POSA would have expected to find a drug-drug interaction between pirfenidone and fluvoxamine. Therefore, the Court concluded that  Sandoz has not met its burden in proving the DDI patents were obvious. 

Infringement

13. Because Genentech have not provided sufficient evidence to show that, more likely than not, direct infringement of the Asserted Claims of the DDI patents will occur, Genentech have not met their burden of proving infringement with respect to the DDI patents. 

14. While the evidence presented at trial confirmed that some physicians will infringe by implementing a dose modification covered by one of the Asserted Claims, the evidence did not establish that Sandoz’s proposed label encouraged, recommends, or promotes infringement of the patented methods. 

In short, Genentech did not meet the burden of proof that Sandoz had infringed on the patents. The Judge rejected Genentech’s claims that Sandoz, infringed on their Esbriet patents.

Decision here.