Much recent debate has centred around TPGS (a water soluble form...

Much recent debate has centred around TPGS (a water soluble form of Vitamin E). The “selling” of TPGS as a DDS on this forum has been almost spam-like in its regularity, generating hundreds of posts since its first mention on 25 November 2016. As the theory goes, Mylan’s plan has been to substitute TPGS for TPM in its TPM daptomycin formulation. It has been  suggested that TPGS is the go-to solubiliser for injectables and claimed that TPGS “owns the injectable development space.”

The enthusiasm for TPGS seems to be a continuation of fervour for water soluble Vitamin E in general. There appears to have been some kind of epiphany for one poster, evident from 29 September 2015, the day after POH announced it was commencing the first of its own animal health trials. Water-soluble Vitamin E as an alternative to TPM was dropped into forum conversation 17 times over the following month.

But returning to TPGS specifically…

Being one of the insultingly-called “intellectually challenged”, I can’t make sense of the theory that Agila/ Mylan's intention has been to simply swap TPGS for TPM in its daptomycin formulation.

One reason, as previously discussed on this forum, is that despite the claims that commercialised TPGS injectables exist, I couldn't find an example, nor was a legitimate example provided when I asked. Perhaps there is, but I was just being treated with contempt. What I did find was a 2016 review of injectable excipients as tested in animal toxicology drug development studies. As it had also been claimed that “Tpgs is the worlds most successful permeator and solubizer”, I had expected TPGS to feature prominently in this review. However, it was only mentioned briefly, twice.  In the first reference, the authors suggested that TPGS was a “poor excipient choice” as it was not a component of any of the well tolerated vehicles. The second reference was to a study in which a compound with TPGS had caused “severe adverse clinical signs and possible allergic reaction”.

This has raised several questions for me:

Given that TPGS was assessed as a poor excipient choice for IV bolus injectables, why would either Agila Strides’ scientists or Mylan decision makers assume that a daptomycin injectable formulation with TPGS would be successfully developed and approved?

Given that 1) the Agila division of Strides was a well-established, large, global specialist in sterile injectables when it signed R & D and licensing agreements with POH in 2011 and 2012 and given that 2) TPGS was recognised as a pharmaceutical solubilizer two decades ago and has been the subject of many papers and patents since, why the need for first an R & D and then a licensing agreement with POH to use TPM? Why not just develop the daptomycin formulation with TPGS from the beginning? Why then file a patent for an improved daptomycin formulation using a tocopheryl phosphate hydrolysate mixture (TPM)? And why then persist with prosecution of the TPM daptomycin patent? Why not just file a patent for an improved daptomycin formulation using d-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) if that’s what you are planning to develop and protect?

I note that, along with the promotion of TPGS as a direct substitute for TPM, the arbitration with Mylan has been characterised as a negative judgement on TPM and patents related to TPM. More specifically, it was argued that any success in claims by POH would in no way reflect the validity of TPM, yet non-success of claims is supposed to be proof of the invalidity of TPM and its patents.

Being one of the insultingly-called “intellectually challenged”, I can’t make sense of this either.

In its arbitration claims, POH claimed that there had been “breaches of confidence” with respect to its IP. If my patent was filed and published, but it infringed someone else’s pre-existing patent, that might mean the rejection of my patent by the patent office or it might mean I’ll be taken to court if I commercialise my patented product, but it surely isn't a “breach of confidence”, as what I infringed was already public knowledge?

Earlier this month I posted about two recent court cases involving theft/disclosure of trade secrets (trade secrets, like patents, are a form of IP and biotechs and pharma use a combination of both for IP protection). The trade secrets in these court cases included research data, manufacturing processes and formulation know-how.

If a collaborative partner deliberately or negligently filed a patent which included the other partner’s trade secrets, this could be considered a breach of confidence with respect to its partner’s IP. I am still of the opinion that this was what was at the heart of the dispute between POH and Agila/Mylan. However, even if claimed POH “know-how” was disclosed in Agila’s patent, it would seem to have been specific to TPM/daptomycin. It doesn’t seem to have negated the patentability of TPM in any type of injectable, because POH has continued with development of a select number of other TPM injectables, including propofol in collaboration with Terumo.

Consequently, I don’t share the opinion that this arbitration decision should be seen as a judgement on TPM or other patents related to TPM.

Finally, on the subject of patents, FullMoonFever has speculated that POH's case might have fallen down because, in his opinion, its Carrier patent fails to identify its relationship to pharmaceutical actives. I note that this has not been the view of the USPTO, with respect to TPM/daptomycin and with reference to Gavin et al. US20090036354 A1.