McSwiggen Patents not Fundamental

Alnylam recently issued a press release regarding the upholding of a European patent (the ‘McSwiggen’ patent EP 1423406) that it had inherited from Merck as a result of the $175M+ January deal.  Given that Alnylam called the patent ‘critical for the development and commercialization of all RNAi therapeutics’, I thought it would be worthwhile pointing out that while valuable, it is by no means to be considered a fundamental RNAi trigger patent. 

The reason is that the patent claims contain a number of important limitations.  Remember that for an RNAi trigger to infringe, it would need to fulfill each of the various specifications.  Here is the main claim with my annotations in red highlight:

1. A chemically modified short interfering nucleic acid (siNA) molecule that down-regulates

expression of a target gene by RNA interference (RNAi), wherein:

a. the siNA comprises a sense strand and a separate antisense strand wherein said

antisense strand comprises a sequence that is complementary to RNA of the target gene

and wherein the sense strand comprises a nucleotide sequence that is complementary

to the antisense strand,

b. each strand of the nucleic acid molecule is independently 18 to 24 nucleotides in length

and the siNA duplex comprises 17 to 23 base pairs;

This encompasses most canonical (Tuschl-type) RNAi triggers, but not Dicer-substrates for example (means it already does not apply to Dicerna’s and Arrowhead’s Dicer-substrate RNAi triggers)

c. 10 or more pyrimidine nucleotides of the sense and/or antisense siNA strand are

chemically modified with 2’-deoxy, 2’-O-methyl or 2’-deoxy-2’fluro nucleotides,

10 or more modifications (on pyrimidines at that) is a lot, but not unprecedented.  Tekmira’s use of RNAi triggers utilizes fewer modifications since they do not rely so much on them for stabilization purposes; however, conjugate approaches such as DPCs and GalNAc-siRNAs are usually heavily modified

with one or more phosphorothiate internucleotide linkages and/or a terminal cap molecule

at the 3’-end, the 5’-end, or both of the 3’ and 5’-ends, being present in the same or

different strand.

A single, terminal phosphorothioate linkage is often employed in RNAi triggers for apparent stability reasons, although I have not actually seen a study that this is actually beneficial; self-delivering RNAi triggers often use more extensive phosphorothioates in addition to an already heavy use of modifications.  ‘Caps’ are used for stability reasons and to increase ‘guide’ over ‘passenger’ strand loading specificity. This is a nice tool, but not essential. For example a UNA (usiRNA) modification at the 5' terminus would do the same.

In sum, the upheld McSwiggen patent has just too many modifications so as to present Alnylam’s competition headaches.  Most affected will be self-delivering RNAi triggers and RNAi trigger conjugates.  In fact, Alnylam may have needed the patent the most and I’m wondering whether it also needed it to do the deal with Genzyme-Sanofi.  Remember both the Alnylam-Genzyme and Alnylam-Merck deals were basically announced on the same day.

And no, this is no evidence that Alnylam's patent estate covers 'usiRNAs' as the company went to pains to point out in the press release.

Marina Biotech to Stage Comeback

Arcturus Therapeutics Acquires usiRNA Technology from Marina

Today, Marina Biotech announced that it is assigning, i.e. is selling usiRNA technology to San Diego RNAi Therapeutics start-up Arcturus Therapeutics.   In addition, the company detailed recent progress in its patent estate encompassing various RNAi trigger- and delivery-related technologies.  Based on these accomplishments, and after extending the maturity date of a critical loan to 2014, it now wants to resurrect itself as a real biotech company by raising capital and relocating to, you guessed it, Cambridge, Mass.  

The usiRNA modification arguably allows you to circumvent the Tuschl siRNA structure and related patent estate by Alnylam and is claimed to even improve upon the Tuschls by allowing for greater specificity.   In addition to Arcturus and Marina, Tekmira, and likely Arrowhead Research (through Roche), have access to such RNAi triggers.

Financial details of the transaction were not disclosed.  Through the assignment of the patents, Arcturus stands to collect the milestone and royalty streams from Marina’s existing licensees.  This includes Tekmira which in its quarterly filing disclosed this week that it would have to pay $3,250,000 in milestones plus single-digit royalties for the technology.  Although these numbers pale in comparison to what Alnylam has asked for RNAi trigger licenses in the past, this suggests that the undisclosed financials and likely upfront payment by Arcturus should have been substantial for a company like Marina…at least enough to continue to pay its patent prosecution and other bills. 

How Arcturus paid for it is unclear to me given that its first significant capital raise involved merely $1.3M.   

For Arcturus the deal seems to make a lot of sense.  If the usiRNA workaround theory holds up, you would be very hard pressed to find such inexpensive RNAi trigger IP (because from a distressed seller) allowing you to broadly go after your targets of choice.  Obviously, this is to complement the liposomal delivery technology on which it was founded.  With the right financial support and scientific talent, Arcturus will be an interesting story to follow.

The Time for the U(nusual)siRNA Strategy Has Come

As Tekmira and Arrowhead Research will unveil their next RNAi Therapeutics development candidates later this year, an interesting question will be whether these will involve one of their RNAi trigger options that some consider to be unencumbered by fundamental IP related to traditional designs (esp. the Baulcombe and Tuschl II IP).  These decisions could have important strategic consequences for the competitive landscape, from targets and indications to Big Pharma involvement.   

Support for freedom-to-operate claim

One of these designs is the usiRNA from Marina Biotech.  These comprise at least one ‘unlocked’ nucleic acid monomer (UNA) in the double-stranded RNA molecule.  While I have reservations about the scientifically tenuous claim (see here why) that UNAs are not to be grouped with most of the other nucleotide modifications for RNAi use because they lack an intact ribose group, usiRNAs were held to be sufficiently non-obvious and of specific utility that the USPTO issued fairly broad claims in 2012.  Moreover, Marina Biotech once commissioned an external IP lawfirm perform a freedom-to-operate analysis on usiRNA, and (surprise, surprise) came to the conclusion that, indeed, usiRNAs have FTO.

Overcoming target picking limitations

This view seems to be shared also by others in the industry. Notably, Roche RNAi (now part of Arrowhead Research) in 2009 gained access to Marina’s usiRNAs, meroduplex siRNAs, and Dicer-substrate RNAi triggers.  This came as a surprise given that Roche had spent over $300M just two years earlier to gain access to RNAi trigger IP held by Alnylam.  Given that none of the three licensed RNAi trigger forms and related IP poses any FTO threat to traditional Baulcombe-Tuschl designs, the most likely explanation for the move is that it was about allowing the company to escape the target picking limitations under the license from Alnylam.  This included the 31 targets exclusively held by Novartis, some Tekmira exclusive target picks, and some targets pursued by Alnylam that Alnylam exempted from competition.  Whether the last of Alnylam’s Big Pharma licensees, Takeda, might pursue a similar strategy is an interesting question.

Facilitating platform partnerships

When Alnylam and ISIS sued Tekmira for infringing on their RNAi trigger IP by collaborating with Bristol-Myers Squibbs on RNAi delivery, it became a priority for them to have access to or control over non-Alnylam RNAi triggers.  As a consequence, they obtained an exclusive license to Halo-Bio’s multivalent RNAi triggers (more than two strands).  Subsequently, they gained access to Marina’s usiRNAs, including the ability to sublicense.   This now puts them in the position to engage in platform partnerships with Big Pharma companies that do not have access to Alnylam IP.

The same strategy would likely also apply to Arrowhead Research with its various RNAi trigger options that it inherited from Roche, especially if Alnylam provided Roche with only product-specific sublicensing rights, if at all.  As RNAi Therapeutics enjoys a return of pharmaceutical interest, this one-stop-shop option by the two leading delivery companies could be critical to bringing new companies into the space.

And for Alnylam, these developments would not only diminish the royalty it might earn from licensing its IP, they could undermine their own product candidates, including ALN-PCSK9 (hypercholesterolemia) and ALN-AT3 (hemophilia).  Accordingly, the preclinical data strongy suggest that subcutaneous DPCs can do everything that Alnylam’s GalNAcs can do, only much more potently and with less frequent dosing. 


 

Marina Biotech Finds Success with Local Bladder Cancer Approach

Marina Biotech this week reported pre-clinical data supporting the use of local, intravesicular siRNA delivery for the treatment of nonmuscle invasive bladder cancer. The publication in Molecular Therapy comes weeks after this early-stage program was partnered with Swiss pharmaceutical Debiopharm which will be responsible for funding the rest of the development.

According to the National Cancer Institute, there are about 70,000 new cases of bladder cancer in the US alone, most of them related to smoking. Because bladder cancer typically starts at the epithelium lining exposed to the urine, simple surgical resection is often sufficient to stop the disease in its tracks. Unfortunately, in some cases the cancer recurs and progresses into a more aggressive, muscle-invasive form of cancer contributing to the 14,700 deaths from bladder cancer annually (US number). Current strategies to prevent recurrence include the instillation of immuno- and chemotherapeutics into the bladder. When this fails, the bladder often has to be removed. Clearly, more treatment options are needed to limit the progression of bladder cancer into the more aggressive forms and maybe also to provide an alternative for bladder removal once more aggressive cancers have developed.

In the present study, Seth and colleagues first screened a range of RNAi triggers against the cancer-related genes polo-like kinase 1 (PLK1) and survivin and were able to demonstrate that Marina’s usiRNA chemistry platform allows for very satisfactory knockdown efficacies with IC50 values in the 10 to 30pM range (bladder cancer cell lines in tissue culture). This triggered widespread apoptosis and, in the case of PLK1, a strong reduction in cell viability. The data therefore add to the notion that PLK1, incidentally also the target in Tekmira’s phase I clinical program TKM-PLK1, may be the single-most promising RNAi cancer target, a view apparently shared by Marina scientists as evidenced in the Discussion part of the paper. Nevertheless, survivin may still be a highly desirable drug target for sensitizing cancer to chemo- and radiation therapies.

The selected siRNAs were then formulated into positively charged multilamellar liposomes of around 100nm. Due to the negatively charged proteoglycan-rich urothelium, a formulation with a lipid containing a guanidinium group was deemed particularly promising in being able to penetrate the 6-7 cell-layered urothelium. Accordingly, these formulations, when instilled into the bladder, were able to very efficiently suppress the growth of nonmuscle invasive bladder cancers in mouse models of the disease. Although equally highly efficient in vivo knockdowns were reported, 90-95% with 1mg/kg (relative to body weight), in my mind there are still some unanswered questions as to how much of that merely reflected the reduction in the size of the tumor.

In terms of safety, no untoward reactions to the formulations were reported. One important reason for this should be the lack of systemic exposure from such treatment. The authors also stated that they were not able to find evidence of innate immune stimulation despite careful investigation. Ideally this analysis would have included a positive control, but then again, also taking into account the 5’ RACE analysis for sequence-specific target cleavage, the overall evidence strongly supports that RNAi knockdown was a main contributor to the in vivo efficacy. Actually, in the case of bladder cancer, having a bit of local immune stimulation may very well be a good thing as I was surprised to learn that bathing the bladder with a solution containing the Calmette-Guerin bacterium (BCG), the famous vaccine against tuberculosis, is part of the current standard of care for superficial bladder cancer and is thought to work by stimulating the immune system. Who knows, Marina may even want to adapt BCG to trans-kingdom RNAi for bladder cancer to combine the RNAi and BCG mechanisms of action into a single agent.

Study Adds yet Another Indication Suitable for Current RNAi technologies

Marina Biotech has made it into an art to select development programs amenable to their current technologies. Given the challenges of systemic RNAi delivery, in a relatively short period of time, the company has already identified and progressed three cancer applications where local approaches can probably be used: familial adenomatous polyposis (FAP; ingested trans-kingdom RNAi), bladder cancer (intravesicular LNP), and most recently malignant ascites (intraperitoneal LNP). Together with developments elsewhere in the field, this clearly shows that the time for RNAi Therapeutics is Now: a range of solid cancers (e.g. liver, lung, FAP, bladder, melanoma), hypercholesterolemia, hemorrhagic fever viruses (Ebola, Marburg), TTR amyloidosis, PHN, AMD, Huntington’s disease etc etc.

While Alnylam Focuses Suit on Whitehead and UMass, a New Tuschl Loophole Approach Gains Traction

Not a day goes by in RNAi Therapeutics land without hearing the sounds from the RNAi trigger IP battle grounds. Today is no exception…

Wading through the court documents from the Alnylam-Max Planck suit on how the Whitehead prosecuted the Tuschl I (T-I) patent application (aka the 'Tuschl Tussle'), it struck me that while it was Whitehead, their hired patent counsel, and UMass that apparently conceived of the strategy of how to incorporate data from the T-II patent into T-I against the interests of Alnylam and Max Planck, the MIT seemed to merely go along unwittingly. As a result, MIT not only became a victim in that they were deprived of the benefits from the therapeutic agreement they were part of with Max Planck and the Whitehead, which to my knowledge anticipated equal sharing of the profits from therapeutic licenses derived from the combined T-I and T-II estate, but also because they ended up as defendants in the suit.

Perhaps realizing this, Alnylam announced today that it will leave the MIT off the hook in return that they will be bound by any ruling in favor of Alnylam/Max Planck. It could also help drive a wedge between the former co-defendants as the MIT will now feel less fearful about telling their side of the story which could turn out to be quite revelatory. The MIT should have every reason to be unhappy with the Whitehead and the way T-I was handled. The argument that Whitehead, and implicitly, the MIT, aided UMass for political reasons, thereby leaving therapeutic licensing money on the table, never really flew with me since a) institutions just don’t give away money like this, and b) I could never imagine a research institution of the stature of Whitehead as being nationalistic and therefore anti-Max Planck.

While the Tuschl Tussle is going on, there is another Tuschl loophole movement in the field that appears to be gaining some traction. It initially started with mdRNA’s claims that the mere inclusion of a single ‘funny-looking’ nucleotide into an siRNA, unlocked nucleic acids (UNAs), would help it get around the Tuschls. It long cited evidence by outside patent counsel that supposedly supported their belief that they had freedom-to-operate in the RNAi trigger space. The news that Quark Pharmaceuticals had just initiated dosing for their 5^th (!) clinical RNAi program for a neuroprotective agent of the eye, it reminded me of their similar claims about ‘proprietary siRNAs’. To find out about the nature of these claims, I looked up what potentially applicable patent applications they had filed, and came up with the following main claim:

"1. A compound having structure (IX) set forth below:

(IX) 5' (N)x - Z 3' (antisense strand)

3' Z'-(N')y- z" 5' (sense strand) wherein each of N and N' is a ribonucleotide which may be unmodified or modified, or an unconventional moiety; wherein each of (N)x and (N')y is an oligonucleotide in which each consecutive N or N' is joined to the next N or N' by a covalent bond; wherein Z and Z' may be present or absent, but if present is independently 1-5 consecutive nucleotides covalently attached at the 3' terminus of the strand in which it is present; wherein z" may be present or absent, but if present is a capping moiety covalently attached at the 5' terminus of (N')y; wherein x =18 to 27; wherein y =18 to 27; wherein (N)x comprises modified and unmodified ribonucleotides, each modified ribonucleotide having a 2'-O-methyl on its sugar, wherein N at the 3' terminus of (N)x is a modified ribonucleotide, (N)x comprises at least five alternating modified ribonucleotides beginning at the 3' end and at least nine modified ribonucleotides in total and each remaining N is an unmodified ribonucleotide; wherein in (N')y at least one unconventional moiety is present, which unconventional moiety may be an abasic ribose moiety, an abasic deoxyribose moiety, a modified or unmodified deoxyribonucleotide, a mirror nucleotide, and a nucleotide joined to an adjacent nucleotide by a 2 '-5' internucleotide phosphate bond; and wherein the sequence of (N)x is substantially complementary to the sequence of (N')y; and the sequence of (N')y is substantially identical to the sequence of an mRNA encoded by a target gene."

As the red highlight shows, the ‘proprietary’ claim of the Quark siRNAs rests on the sense/passenger strand similarly containing at least one ‘funny-looking’ nucleotide. I was disappointed, however, that the specifications did not explain why this should have any unique advantages. Since in addition to novelty (that's where they will likely try to focus their arguments on), a patent has to also fulfill the demands of non-obviousness and utility, I have my serious doubts that this and the usiRNA patent applications will stand up to closer scrutiny, and if they did get by any patent offices, Alnylam would ultimately challenge them. It suggests, however, that while patent protection for these RNAi triggers is unlikely, a number of players increasingly view this strategy as a way to at least gain independence from the Tuschls. The exact reasoning behind this is mysterious to me, since these modifications should already be explicitly covered by the Tuschls when they refer to 'nucleoside analogues' which usiRNAs are. And even if the Tuschls did not explicitly mention them, it would appear obvious that an siRNA is an siRNA whether it contains a limited number of ‘funny’ nucleotides or not.

As I said, I have yet to hear a convincing argument by the companies what their belief is based on. Just stating that they believe so is not enough to convince investors and potential partners. I am always willing to listen to such arguments.