API and IP Newsletter

 Contents

• Patent applications filed by Zydus Lifesciences Limited

• General information

• FDA Grants Accelerated Approval to Takeda's Iclusig for Ph-Positive Acute Lymphoblastic Leukemia

• Patent case numbers rising at UK High Court

• Intellectual Property

• Semaglutide  Oral dosage: T 1777/21 (GLP-1 peptide dosing/NOVO NORDISK)

Patent applications filed by Zydus Lifesciences Limited

We follow patent applications filed by Indian companies.

This week we analysed patent applications filed by Cadila Healthcare Limited.

Cadila filed about 46 PCT applications in last five years and most of them are related to their proprietary molecules. 

Cadila Healthcare Ltd., is renamed as Zydus Lifesciences Ltd, but IP Owner is Cadila Healthcare Ltd. 

Part of the analysis is published below. 

Publication Number	Publication Date	Comments
WO2021048809A9	2023-01-19	This patent family relates to proprietary molecule of Zydus, ZYIL1. Zydus Lifesciences has launched a Phase 2 trial to test its experimental anti-inflammatory therapy ZYIL1 in amyotrophic lateral sclerosis in Q3 2023.  There are various agents from competitors (MCC950, CY‐09, OLT1177, Tranilast, Oridonin, NT‐0167, etc) in various stages of clinical development that directly target NLRP3.
WO2022180612A1	2022-09-01	This family relates to proprietary molecule Saroglitazar. It covers an orodispersible formulation of Saroglitazar. Zydus Lifesciences recently entered into a co-marketing partnership with Lupin for saroglitazar. Lupin will market saroglitazar under the brand name Linvas. Linvas are tablets and this patent family relates to ODT.  These orodispersible tablets are generally for elderly patients, they are solid unit dosage forms like conventional tablets, but are composed of super disintegrants, which help them to dissolve the tablets within a minute in the mouth in the presence of saliva without any difficulty of swallowing.
WO2022157633A1	2022-07-28	This family relates to desglymidodrine.  Desglymidodrine being an active metabolite of midodrine and having a chiral centre, there have been attempts to obtain individual enantiomers of desglymidodrine, to investigate the biological activities of the racemic compound and the individual enantiomers. Zydus might be working on strategies around midodrine.
WO2022149010A1	2022-07-14	This patent family relates to proprietary molecules of Zydus. The present invention describes novel compounds as autotaxin (ATX) inhibitors for treatment and prophylaxis of conditions or a disorder caused by ATX activation or increased concentration of LAP and also describes pharmaceutical compositions.
WO2022058896A1	2022-03-24	This patent family relates to novel compounds. The use of compounds are for the treatment/mitigation or regulation of metabolic disorders or other diseases or conditions mediated by low molecular weight protein tyrosine phosphatases (LMPTP).  This family or the compounds claimed in this family could be the least interesting family for Zydus among others noticing the way it is being prosecuted.

General information

FDA Grants Accelerated Approval to Takeda's Iclusig for Ph-Positive Acute Lymphoblastic Leukemia

The FDA has granted accelerated approval to Takeda’s supplemental New Drug Application for Iclusig (ponatinib) plus chemotherapy to treat adults with newly diagnosed Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL).1,2 Iclusig is the only pan-mutational, third-generation tyrosine kinase inhibitor (TKI) that targets BCR::ABL1, an abnormal tyrosine kinase expressed in Ph-positive ALL and chronic myeloid leukemia (CML). Iclusig can also treat all known single, treatment-resistant mutations, including T315I.

News here.

Patent case numbers rising at UK High Court

The number of newly filed patent cases at the UK High Court rose by over 30% during 2023, after an all-time-low in the previous year. In addition, the UK judiciary introduced a new cost-cap system in early 2024, which aims to appeal to mid-tier litigants.

News here

Intellectual Property 

Semaglutide  Oral dosage: T 1777/21 (GLP-1 peptide dosing/NOVO NORDISK)

The patent proprietor Novo Nordisk A/S filed an appeal against the decision of the opposition division revoking European patent No. 2991671 ie EP 2991671.

Claim 1 of reads as follows.

"A solid composition comprising a GLP-1 peptide and an enhancer which is sodium N-(8-(2-hydroxybenzoyl)amino) caprylate (SNAC) for use in the treatment or prevention of type 2 diabetes by oral administration, wherein

a) said peptide has plasma half-life in humans of at least 60 hours;

b) said composition is administered at least 3 times; and

c) said composition is administered such that the ratio between the plasma half-life in days in humans of said peptide and the dosing interval in days of said composition is more than 2:1."

The  Closest prior art for obviousness discussions:

1. Document D10 (WO 2013/139694 Al ) was suitable as a starting point for analysing inventive step.

2. Document D10 demonstrated that GLP-1 could be bioavailable when delivered orally to dogs in a daily dose, but did not provide any information on the resulting GLP-1 plasma levels, their variability or any therapeutic effect. Moreover, while dogs were suitable for testing bioavailability in general, they were not appropriate as the basis for an assumption on the possible therapeutic effects of GLP-1 peptides.

3. The similarity between the protocol used for the bioavailability testing in Assay (II) of document D10 (page 38 ff.) and the claimed dosage regime was a mere coincidence, as effects in dogs could not be correlated with those in a human patient. The half-life for GLP-1 peptides such as semaglutide differed greatly between dogs and humans.

4. In humans it was around 160 hours (document D9, first sentence), whilst in dogs it was around 60 hours. However, the half-life of a therapeutic agent was relevant when designing or testing a dosage regimen. The skilled person would not have considered the protocol used in dogs in document D10 to be relevant to the success of the treatment as claimed. The treatment protocol provided in document D10 was a research tool to determine bioavailability, not a therapeutic dosage regimen. 

5. The administration of a daily dose of GLP-1 peptide for five consecutive days was designed to increase the statistical relevance of the study while keeping the number of experimental animals low. In addition, there was no evidence of elevated blood glucose levels in the dogs tested.

List of other documents discussed during appeal proceedings are as follows. 

D4	Study NCT01686945; April 15, 2013; Clinical Trials.gov archive; U.S. National Library of Medicine; 8 pages
D5	WO 2012/080471 Al
D7	Aungst B. J.; The AAPS Journal (2012); Vol. 14(1): 10-18
D9	Nauck M. A. et al.; Diabetologia (2012); Vol. 55, [Suppl 1]:S7
D10	WO 2013/139694 Al
D19	Edmonds D. J. et al.; Annual Reports in Medicinal Chemistry (2013); Vol. 48:119-130
D21	EU Clinical Trials Register EudraCT Number: 2012-004994-16; https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-004994-16/DE; 2013-07-30; 7 pages
D22	Study NCT01923181; version 1, published August 15, 2013; Clinical Trials.gov archive; U.S. National Library of Medicine; 14 pages
D26	González Brao M.; Meeting Report; Drugs of the Future (2012); Vol. 37(12):871-874
D47	Steinert R. E. et al.; Am J Clin Nutr (2010); Vol. 92:810-817.
D48	Study NCT02014259; version 1, published December 12, 2013; Clinical Trials.gov archive; U.S. National Library of Medicine; 5 pages
D50	Tyagi P. et al.; J Control Release (2018); Vol. 287:167-176
D51	Dahlgren D. et al.; Eur J Pharm Biopharm (2019); Vol. 142:411-420
D52	Figures presenting plasma concentration; submitted by the appellant with its reply to the notice of opposition; 1 page
D53	FDA News release; "FDA approves first oral GLP-1 treatment for type 2 diabetes"; September 20, 2019; https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-glp-1-treatment-type-2-diabetes; 3 pages
D54	Helfand C.; "Novo Nordisk wins FDA green light for 'holy grail' diabetes drug Rybelsus"; 20 September 2019; https://www.fiercepharma.com/pharma/novo-nordisk-wins-fda-green-light-for-holy-grail-oral-semaglutide; 4 pages D58: Declaration of Flemming S. Nielsen; 22 April 2021; 4 pages

Objective technical problem

The objective technical problem is the provision of an effective oral treatment (or prevention) of type 2 diabetes with a GLP-1 peptide having a long plasma half-life.

The problem has been solved.

Obviousness

1. From the bioavailability studies provided in document D10, which has been identified as a suitable starting point, the skilled person knows that daily administration for five consecutive days will result in a certain plasma level of semaglutide.

2. It was known in the art that semaglutide is bioavailable when administered orally together with SNAC (documents D10; D19, page 122, penultimate paragraph; or D47, abstract) and that GLP-1 peptides, when present in plasma, have pharmacological effects suitable for the treatment of type 2 diabetes (documents D9; D10, page 13, last paragraph; D19, page 120; or D26, page 871, right-hand column).

3. The skilled person would have been cautious, in view of the prior art relating to the oral administration of semaglutide. Document D19, a review article, reports that formulating GLP-1 peptides for oral administration to deliver reasonable bioavailability with low interpatient variability is a challenge (page 121). 

4. However, document D19 goes on to discuss some strategies for addressing this issue, including the use of GLP-1 peptides with a longer half-life, and permeability enhancers such as SNAC. Document D19 reports on page 122, paragraph 2 that oral administration of semaglutide with SNAC resulted in a (low) mean 1.4% bioavailability with considerable variability in exposure. 

5. Referring to document D4 (reference 11 in document D19), this paragraph also mentions that an oral formulation of semaglutide is currently undergoing multidose clinical trials in Europe, albeit at doses considerably higher (up to 60 mg) than those used for the subcutaneous route.

6. Thus, the skilled person would have been aware of ongoing clinical studies, and would have taken into account clinical studies describing oral treatment with semaglutide, such as the study described in document D4, and those in documents D21, D22 and D48.

7. Document D4 describes the phase I clinical trial NCT01686945 investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of daily doses of oral semaglutide, with a delivery agent, given for at least 69 days to healthy male subjects and male subjects with type 2 diabetes.

8. Document D21 describes the multidose clinical phase II trial EudraCT: 2012-004994-16, which compares the efficacy on glycaemic control of 2.5, 5, 10, 20 or 40 mg of orally administered semaglutide in a SNAC formulation in subjects with type 2 diabetes. Three dose-escalation schemes using a single end-dose level for 26 weeks of oral administration are compared.

9. Document D22 describes the multiple-dose clinical phase II trial NCT01923181 examining dosage range, escalation, and efficacy for oral semaglutide in subjects with type 2 diabetes (title). The regimen comprises once-daily oral administration of different amounts of semaglutide in tablet form for 26 weeks (table starting on page 4).

10. Document D48 describes the phase I multiple-dose clinical trial NCT02014259, in which healthy subjects and subjects with type 2 diabetes are given a daily oral dose of semaglutide formulated with SNAC, with a dose escalation consisting of 5 days on 5 mg semaglutide followed by 5 days on 10 mg (page 3).

11. Documents D9, D19 and D26 report successful treatment of type 2 diabetes with subcutaneously administered GLP-1 peptides. 

12. In addition, it was known from documents D10 and D19 that oral administration of GLP-1 peptides with low clearance together with SNAC resulted in (plasma) bioavailability of the drug. The step to clinical trials, see D4, D21, D22 and D48, shows that the skilled person would have seriously contemplated the teaching of documents D10, D19 and D26 and would have taken the step to application in patients.

13. Novo Nordisk A/S argued that the data in document D5 disclosed that in many dogs the bioavailability (F) was zero and the standard deviation of bioavailability was greater than the mean. Document D5 shows that, following a single oral dose to dogs, tablets comprising 15 or 20 mg semaglutide and 300 mg SNAC resulted in better bioavailability (Example 1; Tables 9 and 10) than tablets comprising lower (150 mg) or higher (600 mg) amounts of SNAC (Tables 3 and 5), for which a higher percentage of individuals with zero bioavailability could be observed. 

14. However, the Board said, these data are based on a single administration of the drug, and it can be expected that repeated administration, as required for a chronic disease such as type 2 diabetes, would produce even more favourable results.

15. The clinical studies referred to in the present case merely reinforce the skilled person's expectation that the oral bioavailability of semaglutide results in therapeutic treatment.

Conclusion on inventive step

The board decided that the subject-matter of claim 1 lacks an inventive step. 

Patent was revoked.

Decision here