API and IP Newsletter

 Contents

• Recent P-IV filings reported at USFDA websites

• General information

• Dr. Reddy’s Addresses USFDA Inspection Observations

• US FDA continues high pace in April with 26 drug approvals

• Intellectual Property

• T 0147/22 (TAS-102 formulation/TAIHO)

Recent P-IV filings reported at USFDA websites

Drug, Dosage, Strength, RLD, NDA	Date of Submission	Number of filers	Comments
Acalabrutinib Maleate. Tablets 100 mg. Calquence 216387	13-Feb-24	1	This was originally Acerta Pharma's product. In 2016 AstraZeneca acquired a majority equity stake and secured an access to a likely best-in-class irreversible oral Bruton's tyrosine kinase (BTK) inhibitor, acalabrutinib.  Acalabrutinib is estimated to reach potential peak-year sales in excess of $5 billion globally. Five generic companies have earlier filed ANDA for acalabrutinib capsules. One of them could have filed for the tablet.
Avibactam Sodium and Ceftazidime. For Injection 0.5 g/2 g per vial. Avycaz 206494	26-Feb-24	2	Maybe Orchid is one of the ANDA filer based on public domain information. This product enjoys GAIN exclusivity. The two antibiotics represent a brand sales opportunity of USD 350-400mn in the US and a potential launch could happen in FY27.
Bempedoic Acid Tablets. 180 mg. Nexletol 211616	21-Feb-24	9	Very competitive P-IV filing, nine filers on NCE-1 date! Nexletol is approved to help decrease LDL cholesterol in adults with heart disease or heterozygous familial hypercholesterolemia (HeFH)
Bempedoic Acid and Ezetimibe Tablets. 180 mg/10 mg  Nexlizet 211617	21-Feb-24	3	Peak sale estimated to be > $ 2-3 Bn. It's approved to help reduce low-density lipoprotein (LDL) cholesterol, also known as “bad” cholesterol.  OB listed fixed dose combination patent US10912751B2 will expire in 2036, launch prior to 2036 could be challenging. Maybe generics would try to settle the case for the mutually agreed launch date.
Diazepam Nasal Spray. 10 mg/spray. Valtoco 211635	14-Feb-24	1	This is a small product, Valtoco had just over $40 million in sales in 2021. This diazepam nasal spray is indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity.
Ferric Carboxymaltose. Injection. 500 mg/10 mL. Injectafer 203565	22-Feb-24	1	Generics have already settled other strengths. One could see settlement with this strength too. Injectafer is indicated for the treatment of iron deficiency, anaemia.
Rimegepant Sulfate. Orally Disintegrating Tablets. 75 mg. Nurtec ODT 212728	27-Feb-24	7	This medication is used to prevent or treat migraine. The drug could enter blockbuster territory in 2023 with sales of $1.38 billion and analysts predicted $1.85 billion in 2024. Markush claim is valid till 2030 and specific compound claim is valid till 2033. Patent term extension possible for Markush claim and hence generic entry prior to 2035/2026 looks difficult today.
Suvorexant. Tablets. 5 mg, 10 mg, 15 mg, 20 mg. Belsomra 204569	04/03/24	1	Belsomra is used to treat insomnia in adults who have trouble falling asleep, staying asleep, or both. The compound is covered in US7951797 and it would be valid till November 2029. Any generic launch possibility of Suvorexant prior to November 2029 could be unlikely. However, Merck’s Belsomra have had achieved limited success so far. In 2023 it was about $320 million product, it was approved in 2015.
Technetium TC-99M Tetrofosmin Kit. Intravenous Injection. 1.38 mg/vial. Myoview 30 mL 20372	20-Feb-24	1	Myoview is indicated for scintigraphic imaging of the myocardium following separate administrations under exercise and or resting conditions.  It was first approved in 2005 in US. This is relatively very small product in US and could be less than USD 50-60 mio sale based on public domain information.  The composition patent covering a radioprotectant chosen from ascorbic acid with a biocompatible cation is listed in Orange Book which would expire in 2030 and hence generics had to file P-IV certificate.

General information

Dr. Reddy’s Addresses USFDA Inspection Observations

Dr. Reddy’s Laboratories Ltd. has announced the completion of a routine USFDA GMP inspection at their manufacturing facilities in Duvvada, Visakhapatnam, which resulted in receiving two observations. The company has committed to addressing these observations within the required timeline. This regulatory update is crucial for investors tracking the company’s compliance and operational progress.

News here.

US FDA continues high pace in April with 26 drug approvals

In April, the U.S. FDA approved 26 new drugs, the sixth-highest monthly total going back to 2016. This is slightly lower than March’s record-setting 30 approvals, the highest count in BioWorld’s records. By comparison, the FDA approved an average of about 16 drugs per month in 2023, 12.5 per month in 2022, and 17 per month in both 2021 and 2020.

News here

Intellectual Property 

T 0147/22 (TAS-102 formulation/TAIHO)

This invention relates to TAS-102. 

TAS-102 ie trifluridine/tipiracil (FTD/TPI), sold under the brand name Lonsurf, is a fixed-dose combination medication that is used as a third- or fourth-line treatment of metastatic colorectal cancer or gastric cancer, after chemotherapy and targeted therapeutics have failed

The decision under appeal is the opposition division's decision in favor of Teva revoking European patent Number EP2815753. This patent was issued to Taiho. 

Taiho appealed the decision at The Board of Appeals at EPO. The Board of appeals considered the following documents as prior art documents while rendering the decision.

D1 EP 1849470A1

D2 Appellant's (Taiho patent proprietor) letter to the examining division dated 21 December 2015.

D3 H.A. Lieberman et al., Pharmaceutical Dosage Forms - Tablets, vol. 1, 2nd edition, 1989, 93-110 and 173-177

D7 Additional comparative tests dated 15 April 2020 

D8 R.C. Rowe et al., Handbook of Pharmaceutical Excipients, 6th edition, 2009, 129-133 

In the decision under appeal, the opposition division at the first instance concluded, among other things, that the subject-matter of the patent as granted did not involve an inventive step starting from D1 as the closest prior art. 

Six Auxiliary requests filed, the Auxiliary request 4 was finally contested and which had two claims, which read as follows:

"1. An orally administrable pharmaceutical composition consisting essentially of

(a) alpha,alpha,alpha-trifluorothymidine (FTD) and 5-chloro-6-(2-iminopyrrolidine-1-yl)methyl-2,4(1H,3H)-pyrimidine dione hydrochloride (TPI) as active ingredients at a molar ratio of 1:05,

(b) a sugar having a critical relative humidity of 85% or more at 25°C as an excipient, wherein the sugar having a critical relative humidity of 85% or more at 25°C is one or more selected from lactose, sucrose, mannitol, and erythritol,

(c) a disintegrating agent which is partly pregelatinized starch, and

(d) additives selected from excipients other than the sugar having a critical relative humidity of 85% or more at 25°C, 0.001 to 5% by mass in the total composition of a binder selected from hydroxypropyl cellulose, hypromellose, and polyvinyl alcohol, 0.001 to 3% by mass in the total composition of a lubricant selected from hydrogenated oils, sucrose fatty acid esters, and stearic acid, flavoring agents, colorants, and taste-masking agents, wherein the content of the sugar having a critical relative humidity of 85% or more at 25°C is 3.6 parts by mass or more based on 1 part by mass of alpha,alpha,alpha-trifluorothymidine (FTD) ,

wherein the proportion of the sugar having a critical relative humidity of 85% or more at 25°C is 90% by mass or more in the total excipient, wherein the content of the disintegrating agent is from 3 to 7% by mass in the total amount of the pharmaceutical composition, and

wherein the pharmaceutical composition is in a formulation form of a granule, a compression-molded product, or a mixture."

"2. An orally administrable pharmaceutical formulation comprising the orally administrable composition according to claim 1, wherein the composition is coated."

The combination of FTD and TPI at a molar ratio of 1:0.5 is known as "TAS-102" 

The binder hypromellose is also known as hydroxypropylmethylcellulose.

Inventive step (Article 56 EPC) - 

Patentee argued

1. FTD is a very potent active agent administered at very low doses. 

2. For this reason, it is essential that it be dosed with high precision. 

3. The problem that arises with FTD-containing formulations is that FTD hydrolyses easily. Therefore, humidity may produce undesirable variations in the amount of FTD in a formulation, with a corresponding impact on the efficacy and safety of the therapeutic treatment. 

4. The patent is intended to solve this problem by providing an orally administrable formulation of TAS-102 which does not experience significant variations in its amount of active ingredients, even when stored under high-humidity conditions 

The closest prior art

It was common ground between the parties that D1, in particular Formulation Example 1, was the closest prior art.

D1 is a patent application intended to provide a suitable dosage regime of TAS-102 for treating cancer by oral administration. D1 proposes administering TAS-102 two to four times daily at a dose of 20 to 80 mg/m2/day. On page 6, D1 discloses Formulation Example 1, which is a tablet suitable for the proposed administration of TAS-102. The tablet contains the following ingredients (percentages by mass have been added by the Board to facilitate subsequent discussion):

Ingredient	Amount (mg)	Mass%|
FTD	20.00	15.0
TPI	9.42	7.1
Lactose	70.00	52.5
Crystalline cellulose	3.50	2.6
Magnesium stearate	1.00	0.75
Talc	1.00	0.75
Cornstarch	3.50	2.6
Hydroxypropylmethylcellulose	25.00	18.7
Total weight  (per tablet)	133.42	100.0

D1 is silent on the stability problems of TAS-102 formulations during storage due to the sensitivity of FDT to hydrolysis. D1 does not disclose any information on Formulation Example 1 beyond its preparation using the indicated ingredients and corresponding amounts.

With regard to the function of each ingredient in Formulation Example 1, the parties did not call into question that formulation ingredients may have multiple functions. 

The distinguishing features

After a debate,  the Board identifies the following distinguishing features in claim 1:

1. the lactose content is 3.6 parts by mass or more based on 1 part by mass of FTD,

2. the disintegrant is partly pregelatinised corn-starch,

3. the amount of binder does not exceed 5% by mass in the total composition, and

4. the lubricant is selected from hydrogenated oils, sucrose fatty acid esters and stearic acid.

The technical effect

1. The parties discussed two technical effects associated with the distinguishing features. First, the chemical stability of TAS-102 in the formulation, especially under high humidity conditions. This effect is essential to prevent undesirable variations in the amount of TAS-102 during storage. Second, the disintegration time of the formulation. A short disintegration time reflects the ability of the formulation to quickly disintegrate in the patient's oral cavity, even without adding water, thus facilitating ingestion.

2. The assessment of inventive step is based on the stability of TAS-102 as the only technical effect. 

3. The evidence relating to this effect can be found in the comparative tests disclosed in Tables 1, 2 and 6 of the patent and in the table in D7. In those comparative tests, stability was assessed by determining the amount of substances related to TAS-102 that could be found in the formulation after a certain period of storage at 40°C and 75% relative humidity. The lower the amount of related substances, the higher the stability of TAS-102.

4. The data in Table 6 of the patent. Table 6 is reproduced below. It shows the stability results for several TAS-102 formulations after a storage time of two weeks.

5. The table discloses compositions comprising components (a), (b) and (d) as defined in claim 1. 

6. These results firstly show that the addition of a disintegrating agent to the formulation produces a slight destabilisation of TAS-102. Nevertheless, the formulations containing 5% or 10% by mass of disintegrating agents still exhibit acceptable stability levels for storage. The degree of destabilisation is slightly lower in formulations containing corn-starch than in formulations containing partly pregelatinised starch.

7. The data in Tables 1 and 2 of the patent. Tables 1 and 2, reproduced below, disclose the results of stability tests obtained after a storage time of one month.

8. These tables show that lactose, sucrose and D-mannitol are suitable excipients for the formulation of TAS-102. The test designated "Comparative Example" in Table 1 also shows that a high amount of crystalline cellulose (73.55 parts by mass, which correspond to 82% by mass) has a destabilising effect on TAS-102 and produces a total mass of related substances of 1.64%. 

9. This result, however, does not provide any valid information as to the effect of crystalline cellulose when present at a concentration of 2.6% by mass, as in Formulation Example 1.

10. The table in D7, reproduced below, shows results obtained after a storage time of two weeks. These conditions are the same as in Table 6 of the patent.

11. The composition "Base Formulation (D1)" corresponds to Formulation Example 1 in D1. Comparing the total mass of related substances produced in "Base Formulation (D1)" with that of "Additional Comparative Example 1", it appears that hydroxypropylmethylcellulose has no negative impact on the stability of TAS-102, indeed rather the opposite. When the binder is eliminated from the composition, the total mass of related substances increases from 0.59% to 0.71%.

12. In view of the demonstrated technical effect, the objective technical problem can be defined as that of finding a formulation containing TAS-102 which provides high stability of the active ingredients even under high-humidity conditions.

13. The Board is satisfied that this problem is solved by the composition of claim 1. Tables 1 and 2 of the patent show that the sugar excipients in component (b) of claim 1 at sugar/FTD mass ratios higher than 3.6 provide formulations in which TAS-102 is stable. 

14. Table 6 of the patent and the table in D7 show that the presence of 3% to 7% by mass partly pregelatinised starch in those formulations does not cause significant TAS-102 instability. Similarly, the table in D7 shows that the binder hypromellose does not contribute to TAS-102 instability, and Table 6 of the patent shows that 1% by mass of the lubricant stearic acid is not detrimental either. 

15. Contrary to the respondent Teva, the Board sees no reason to realistically conclude that the presence of small amounts of unspecified excipients in component (d) can cancel out the effect shown on the stability of TAS-102. 

16. Furthermore, as the composition of claim 1 is essentially limited to components (a) to (d), and additional components must not affect TAS-102 stability, the Board considers that the evidence on file sufficiently proves that the claimed subject-matter is a suitable solution to the problem posed.

Obviousness:

1. With respect to the obviousness of the solution proposed in claim 1, D1 does not mention the stability problems arising with TAS-102 formulations due to the sensitivity of TAS-102 to hydrolysis. 

2. Accordingly, D1 does not contain any information as to the stability of TAS-102 in Formulation Example 1. It appears from the tests carried out by the patentee Taiho in D7 that Formulation Example 1 exhibits acceptable levels of stability, but this information is missing from D1. 

3. Even if the skilled person measured the stability of TAS-102 in Formulation Example 1 and became aware that it was sufficiently storage stable, the Board fails to see how the skilled person would arrive at a composition as defined in claim 1 when seeking a further formulation providing TAS-102 stability. 

4. The skilled person could not expect that, after drastically reducing the amount of binder from 18.7% to no more than 5% by mass and exchanging corn-starch or corn-starch and crystalline cellulose with partly pregelatinised starch, TAS-102 would remain stable. Therefore, the subject-matter of claim 1 is not obvious from D1 alone.

5. The respondent Teva combined D1 with the common general knowledge in D3 that partly pregelatinised starch is an alternative disintegrating agent to corn-starch. However, D3 does not contain any information relating to the equivalence of these disintegrating agents with respect to their impact on the stability of water-sensitive active ingredients. This would equally apply to the combination of corn-starch and crystalline cellulose as the disintegrating agent.

6. There is also no pointer in any of the cited prior-art documents suggesting that the amount of binder in a formulation can be drastically reduced without significantly affecting the stability of water-sensitive active ingredients.

7. Therefore, the Board agrees with the patent proprietor Taiho that the skilled person had no motivation to modify Formulation Example 1 in D1 so as to arrive at the composition of claim 1.

Therefore, the Board of Appeals concluded that claims 1 and 2 meet the requirements of inventive step as per EPC. 

Decision here