API and IP Newsletter
Contents
Sanofi and Seagen team up to grow a new crop of ADC cancer drugs
What do psychedelic drugs do to our brains? AI could help us find out
DMFs filed by Aurobindo
Aurobindo Pharma filed 9 DMFs in last quarter. A brief analysis of some of their DMF filings is as below
General information
Sanofi and Seagen team up to grow a new crop of ADC cancer drugs
Sanofi’s cancer drug pipeline has only one antibody drug conjugate, the last remnant of a nearly two decade-old research alliance that has not panned out as well as hoped. But ADCs have seen a resurgence in recent years and Sanofi wants to ensure that it’s part of this growing field of cancer treatments, so it’s partnering with ADC specialist Seagen in a multi-drug agreement.
News here.
What do psychedelic drugs do to our brains? AI could help us find out
Psychedelic drugs have long been touted as possible treatments for mental-health disorders like depression and PTSD. But very little is really known about what these substances actually do to our brains—and it can be hard to find out. Understanding how they work could help unlock their potential.
Some scientists are using AI to figure it out. A team at McGill University in Montreal used natural language processing—the technique that allows voice assistants or search engines to work — to study written “trip reports” of drug users’ experiences. The work could shed light on how hallucinogens trigger specific mental states, whether that be euphoria, anxiety, or a sense of being at one with the world.
News here.
Intellectual Property
Enalapril Maleate: Silvergate vs Bionpharma
Silvergate conceded that Bionpharma though does not literally infringe OB listed patents there is an infringement under the doctrine of equivalents ("DOE").
Bionpharma countered that legal bars specifically, prosecution history estoppel, disclosure-dedication, and claim vitiation prevent Silvergate from prevailing on its DOE theories.
On 27 April 2021, district court found Bionpharma’s formulation is not infringing. Matter was in Appeal Court (CAFC).
Patent claim:
1. A stable oral liquid formulation, comprising:
(i) about 0.6 to about 1.2 mg/ml enalapril or a pharmaceutically acceptable salt or solvate thereof;
(ii) a buffer comprising about 0.8 to about 3.5 mg/ml citric acid and about 0.1 to about 0.8 mg/ml sodium citrate;
(iii) about 0.7 to about 1.2 mg/ml sodium benzoate; and
(iv) water;-------
The patent claims sodium benzoate and it must be the marketed product, Bionpharma in their ANDA used methylparaben and propylparaben as a preservative. Let us confine today’s discussion only to this DoE argument.
The preservative limitation in the Asserted Claims requires about 0.6 to about 1.2 mg/mL of sodium benzoate.
Bionpharma's ANDA Product does not contain sodium benzoate; it contains methylparaben and propylparaben.
Dr. Moreton (Bionpharma's expert) agreed that an oral liquid formulation will necessarily contain a preservative in order to mop up any stray microbes that would get in there.
Travis Webb, the formulator of Bionpharma's ANDA Product, testified that methylparaben and propylparaben are used as a preservative, and have the same function as the sodium benzoate in Silvergate's Epaned® product. He further testified that the parabens were selected for Bionpharma's ANDA Product solely because they are antimicrobial preservatives.
Usha Sankaran, Bionpharma's Associate Vice President of Regulatory Affairs, agreed that the function of the methylparaben and propylparaben in Bionpharma's ANDA Product is to be "antimicrobial preservatives."
Methylparaben and propylparaben are structurally similar to sodium benzoate. The parabens are esters of p-hydroxybenzoic acid, whereas sodium benzoate is the sodium salt of benzoic acid.
Patent specification: The patent specification discloses that a paraben or a mixture of parabens can be used as suitable preservatives in the disclosed formulations.
The parabens have a different mechanism of action. They work in different ways than sodium benzoate and have different physical properties as well. (Moreton)
Sodium benzoate is inactive and has to be converted to benzoic acid, at a pH below 5, in order for it to exert its antimicrobial effects. (Moreton)
The optimal pH for the antimicrobial activity of the parabens is in the range of 4 to 8. (Moreton)
A skilled formulator preparing an enalapril liquid formulation would have to consider the relative solubilities of the preservatives because she would have to tailor the manufacturing processes to the properties of the ingredients. (Moreton)
Methylparaben-propylparaben preservatives are lipophilic and less soluble in water. (Moreton). Solubility for methylparaben is 1 part per 400 parts of water while solubility for propylparaben is 1 part per 2500 parts of water. (Moreton) Sodium benzoate on the other hand has higher solubility of 1 part per 1.8 parts of water.
Parabens are soluble in propylene glycol: 1 in 5 for methylparaben and 1 in 3.9 for propylparaben.
A formulator can get parabens into an aqueous solution by using their sodium salts, as Silvergate did in its studies. (Moreton). A formulator can also dissolve the parabens in a co-solvent, such as propylene glycol, as Bionpharma did.
Sodium benzoate does not need a co-solvent to dissolve in water. (Moreton)
Parabens are effective against yeasts and moulds and gram-positive and gram-negative bacteria; they are considered by a POSA as generally antimicrobial and fungicidal. (Moreton)
Sodium benzoate, on the other hand, is only effective under acidic conditions, and the way in which it acts as a preservative is by entering the bacterial cell and inhibiting the fermentation of glucose.
Sodium benzoate is considered bacteriostatic and fungistatic, not bactericidal and fungicidal. (Moreton). It inhibits the growth of microorganisms but does not kill the microorganisms. Dr. Moreton testified that sodium benzoate has antimicrobial effects and exerts effects against yeast at a pH less than five.
Dr. Moreton also testified that, in the oral solution of the ANDA Product, the mixture of methylparaben and propylparaben has antimicrobial effects and exerts effects against yeast.
Bionpharma's ANDA Product maintains a pH between 3.2 and 3.6. The methylparaben and propylparaben are effective at preventing microbial growth for the product in this range.
The Epaned® product (Silvergate product) shows that the sodium benzoate preservative demonstrates antimicrobial effectiveness. It meets the specifications of USP methods and has both antimicrobial and antifungal effects. The Epaned® solution shows an absence of Escherichia coli, or E. coli.
Bionpharma's ANDA Product shows substantially similar efficacy with the methylparaben/propylparaben preservative. The antimicrobial effectiveness meets the same requirements of the USP and Bionpharma's ANDA Product also has an absence of E. coli.
As Bionpharma points out, the relevant inquiry is whether a POSA could identify, from the patent disclosure, the alleged equivalent's existence and suitability as an alternative. Bionpharma has proven that a POSA would have had such an understanding. Dr. Moreton testified that a POSA would know that methylparaben and propylparaben are commonly used together and would be a suitable alternative preservative.
Dr. Moreton further testified that the patent's disclosures demonstrate the parabens' suitability specifically as an alternative to sodium benzoate.
The Court is persuaded that a POSA would understand, based upon the disclosures in the specification, that (1) parabens or a mixture of parabens may be used as a preservative in the claimed formulations; and (2) propylparaben and methylparaben are specifically identified as such suitable parabens.
By disclosing and then not claiming this embodiment, Silvergate is estopped from proving DOE infringement based on it.
On 9 March 2022 Federal Circuit affirmed district court and found Bionpharma’s product non-infringing under Doctrine of Equivalents (DOE)
Decision here.
