API and IP Newsletter
Contents
FDA approval in May 2022
We follow FDA approvals. The objective of this write-up is to study chemistry and understand who would be potentially developing this API.
VTAMA (tapinarof) approved in May 2022.
VTAMA (tapinarof) cream contains tapinarof as the active ingredient.
Tapinarof is an aryl hydrocarbon receptor agonist. It is a medication used for the treatment of plaque psoriasis.
Jefferies predicted tapinarof revenue to ramp up to $50 million in 2023 for its psoriasis label.
(Here). This could be a small product.
Tapinarof is a white to pale brown powder with the following structural formula.
Each gram of VTAMA cream for topical use contains 10 mg of tapinarof in a white to off-white cream.
Chemistry
Several routes to the synthesis of the compound of tapinarof are known in the art.
Chinese patent application CN101648851 describes a route of synthesis via the formation of the (E)-olefin via Horner-Wadsworth-Emmons olefination.
Routes are also known which are via the introduction of the isopropyl group onto a substituted resorcinol derivative via Friedel-Crafts alkylation.
An alternative synthetic approach, similar to known biosynthesis route, was described by Kronenwerth et al. (Eur. J. Org. Chem. 2014, 8026-8028).
Schamp et al. (Tetrahedron, 1973, 29, 3857-3859) discloses a synthesis of simple 2-substituted resorcinols such as 2-methyl-, 2-benzyl- and 2-acetylresourcinol from the corresponding 1,3-cyclohexanediones.
Commercial route is reported in WO2019094934A1, this patent family claims high yielding synthesis with no potential toxicity problems.
Many Indian companies will be developing this simple chemistry. Wavelength is already exporting very small quantities, most probably to potential formulators.
General information
Indian-origin CEO and CFO of Bio-pharma faces class action lawsuit over UTI drug promises
Spero Therapeutics, a Delaware-based clinical-stage bio-pharmaceutical company, faces a class action lawsuit filed by investors who claim they suffered significant losses and damages due to misleading and false statements over a new drug meant to treat Complicated Urinary Tract Infections.
The lawsuit, filed in the Eastern District Court of New York on May 26, 2022, names Spero Therapeutics CEO Ankit Mahadevia, and its Chief Financial Officer Satyavrat Shukla. as the two main defendants.
News here.
J&J takes Aurobindo to court over potential Erleada generic
A group of plaintiffs, including J&J’s Janssen unit and the Sloan Kettering Institute for Cancer Research, filed a lawsuit against Aurobindo on Thursday accusing it of applying to market an Erleada copycat before five patents are up.
In the complaint, the plaintiffs said Aurobindo sent a letter back in April informing them that the company had submitted an abbreviated new drug application (ANDA) for a generic version of Erleada. According to the defendants — Aurobindo and its units Eugia Pharma and AuroMedics — the generic doesn’t infringe on J&J’s patents because it doesn’t contain crystalline Form B of apalutamide, the active ingredient in Erleada.
News here.
Intellectual Property
T 1732/18: Treatment of thrombotic disorders with rivaroxaban (Online 16 May 2022)
EP1845961B1 issued to Bayer. An independent Claim as follows
The use of a rapid-release tablet of rivaroxaban for the manufacture of a medicament for the treatment of a thromboembolic disorder administered no more than once daily for at least five consecutive days, wherein said compound has a plasma concentration half-life of 10 hours or less when orally administered to a human patient.
After compound patent expiration, the most important patent for innovator in Europe will be EP1845961B1. This will expire in January 2026.
This patent was opposed by several opponents. The decision under appeal as the opposition division revoked the patent on 7 February 2018. Patentee (Bayer) appealed.
There are several prior art references cited during the appeal proceedings.
D1: US 2003/0153610 A1
D2: Blood 102(11): American Society of Hematology, Forty-fifth annual meeting program and abstracts, Part 1, Abstract no. 3004 (2003)
D3: Blood 102(11) Part 1, Abstract no. 3010 (2003)
D4: M.E. Aulton (ed.), Pharmaceutics: The Science of Dosage Form Design, 2nd edn., Churchill Livingstone (2002), pages 410-411
D6: Current Topics in Medicinal Chemistry, 1(2), 151-159 (2001)
D8: Janssen Pharmaceuticals, Inc.: Xarelto**(®) Dosing and Transition Management (April 2015)
D11: Pathophysiol Haemost Thromb 33 (Suppl 2), p. 98, Abstract no. PO080 (2003)
D12: Pathophysiol Haemost Thromb 33 (Suppl 2), p. 98, Abstract no. PO081 (2003)
D14: Rowland, Tozer: Clinical Pharmacokinetics: Concepts and Applications, 83-105 (1995)
D15: Pathophysiol Haemost Thromb 33 (Suppl 2), p. 97, Abstract no. PO078 (2003)
D16: Journal of Thrombosis and Haemostasis 3, 514-521 (first published online on 26 January 2005)
D17: Blood 102(11) Part 1, Abstract no. 3003 (2003)
The multi-dose phase I clinical trial described in documents D2 and D11 represented the closest prior art.
The technical problem to be solved was to provide a safe and effective oral dosage regimen of rivaroxaban for the prophylactic and therapeutic treatment of thromboembolic disorders.
In view of the teaching of documents D15 and D17 regarding the sustained effect of single oral doses of rivaroxaban, the person skilled in the art would not have needed inventive skill to establish the dosage regimen of claim 1 (i.e. once-daily administration of a rapid-release tablet of rivaroxaban for at least five consecutive days) to solve this technical problem.
In this write-up we will cover only inventive step aspects in brief.
The disclosure of abstracts D2/D11, referring to the pharmaceutically active compound as "BAY 59-7939", D2/D11 disclosed rivaroxaban.
Starting from the disclosure of abstracts D2/D11, the person skilled in the art seeking to provide an oral dosage regimen of rivaroxaban for the prophylactic and therapeutic treatment of thromboembolic disorders would have consulted further documents providing information on rivaroxaban.
The opponents argued, the subject-matter of claim 1 as granted lacked an inventive step based on the teaching of D2/D11 in light of the common general knowledge. The dosage regimen defined in claim 1 was merely the straightforward result of routine phase II dose-finding studies.
Obviousness discussion
Based on D2/D11 stating that rivaroxaban was a direct factor Xa inhibitor and in development for the prevention and treatment of thromboembolic diseases, the person skilled in the art would have had a general expectation that this drug could provide clinical efficacy for this indication. D2/D11 also reports preliminary favourable results regarding safety in healthy subjects. Thus, there was agreement among the parties that the skilled person would have made the transition from phase I to phase II clinical testing.
The issue to be decided under obviousness is whether the skilled person would have had an incentive and reasonable expectation of clinical success regarding the specific regimen defined in claim 1, i.e. once-daily dosing of rapid-release rivaroxaban for at least five consecutive days, in patients, i.e. subjects at heightened risk for thromboembolism.
The Opponents argued that the disclosure of D2/D11 was consistent with rapid-release dosing. Abstracts D2/D11 also taught that pharmacodynamic effects were still present after 12 hours.
While half-life was usually a guiding factor for determining dosing frequency, the importance of using pharmacodynamic data obtained in phase I trials was also generally recognised. After the phase I study described in D2/D11, the skilled person would not have ruled out once-daily dosing as a viable regimen since no discouraging results had been observed.
In addition, it was known from the pre-published review article D6 that short-term direct inhibition of factor Xa could lead to a sustained downstream biological action and that the therapeutic window of direct factor Xa inhibitors was expected to be relatively large in comparison to other anticoagulants
The board considered that the disclosure of D2/D11 by itself, or in light of common general knowledge, would not have provided motivation to the person skilled in the art to pursue clinical testing of a once-daily regimen of rapid-release rivaroxaban in patients, for the following reasons.
The abstracts D2/D11 relate to a phase I study in healthy volunteers. This was a multiple dose escalation study following up on a phase I single dose escalation study with healthy volunteers
At the effective date of the patent in suit, it had not been shown that rivaroxaban was safe and effective in patients, i.e. subjects requiring therapeutic or prophylactic anticoagulant treatment. Neither had this been shown for the class of direct-acting oral factor Xa inhibitors in general.
Solving the objective technical problem thus involved providing a dosage regimen for rivaroxaban's first medical use in patients. The current case differs in this aspect from the typical situation in other "dosage regimen cases", where development is based on established therapeutic uses of the drugs concerned.
Due to ethical and safety concerns, the person skilled in the art would have adopted a cautious attitude regarding the set-up of first-time dose-ranging clinical studies of a novel anticoagulant in patients since the risk of both bleeding and thrombosis was expected to be high.
Participants in phase I anticoagulant studies are selected to exclude susceptibilities to and potential causes of bleeding. The fact that no bleeding complications had been observed with rivaroxaban in healthy volunteers did not permit drawing the conclusion that the drug would be safe in patients with pathology.
It was known, for instance, that the phase II trial for the direct factor Xa inhibitor razaxaban had revealed serious safety concerns despite positive phase I results.
Before the publication of phase II data, nothing was known about the therapeutic window of rivaroxaban. The therapeutic window of anticoagulants can be narrow, since the same mechanism is responsible for the therapeutic effect (anticoagulation) and the potentially lethal side effect of bleeding. There would have been legitimate concerns that fluctuations in drug concentration might result in either excessive bleeding (due to overdosing) or thromboembolism (due to underdosing).
The skilled person would, therefore, have pursued an approach that minimises such fluctuations. To avoid over or underdosing, they would have considered the half-life of the drug, as this was, in common general knowledge, the fundamental factor in determining dosing frequency (D14).
On this basis, the skilled person would have wanted to select a dosage form and frequency that compensated for rivaroxaban's short half-life (four to six hours according to D2/D11 or three to four hours according to D3/D12).
Considering the short plasma concentration half-life of rivaroxaban known from D2/D11 and D3/D12, the person skilled in the art would have expected that twice- or thrice-daily dosing.
In summary, the serious concerns about safety in the case of a new anticoagulant did not warrant a "try-and-see" attitude for the dosage regimen, and the known, relatively short, half-life of rivaroxaban would not have supported an expectation of success with regard to once-daily dosing of rapid-release rivaroxaban.
The statements in D2 and D11 that relevant changes in the pharmacodynamic parameters were still present after 12 hours or that factor Xa inhibition effects were maintained for 8 to 12 hours at the 5 mg od dose, and "-12 hours" at the 10 mg bid, 20 mg bid and 30 mg bid doses cannot change the conclusions based on general safety considerations and half-life.
This is because it is not possible to infer from these statements that the effects observed would be maintained for longer than 8 to 12 hours and would also suffice to maintain the required level of anticoagulation in a patient at risk of thromboembolism over 24 hours.
Document D6 is a review article (published four years before the priority date of the patent) based on preclinical data of early drug candidates in the class of direct factor Xa inhibitors, not including rivaroxaban.
The opponents also argued that the disclosure of the complementary documents D15/D17 (especially the statement that a sustained effect of BAY 59-7939 on thrombin generation for up to 24 hours had been observed) would have provided the skilled person seeking to solve the objective technical problem with an expectation of success regarding once-daily dosing of rapid-release rivaroxaban.
Once the decision to continue with phase II studies had been taken, there was no pre-determined path which would inevitably have led the skilled person to the dosage regimen defined in claim 1.
Also, the skilled person setting up a phase II clinical trial of a new anticoagulant was not in a routine "try-and-see" situation. Without a reasonable expectation of success with regard to clinical efficacy and safety, the mere wish for patient convenience would not have been sufficient as an incentive for testing an od (Once a Day) regimen of a rapid-release form of the drug.
The information leading to the claimed subject-matter would thus have had to be acquired by the skilled person's own subsequent research.
Even after finding an unexpectedly wide therapeutic window in a study exclusively testing bid or tid regimens, or sustained-release regimens included for patient convenience, the skilled person would not inevitably have taken the decision to switch the dosing frequency. They might just as well have continued clinical development with one of the tested bid, tid or sustained-release regimens that looked most promising in terms of safety and efficacy.
For these reasons, the Board said, the subject-matter of claim 1 involves an inventive step.
Patent was upheld. (here)
