Moderna v. Arbutus Inter Partes Review on LNP Patents: Hearing Transcripts Summary

Research

Update 2020.01.03: It turns out my naive assessment was wrong again. '435 patent is partially upheld and '127 is fully invalidated. Please follow this link for a summary by Markman Advisors.

Valid claims of '435 patent

7. The nucleic acid-lipid particle of claim 5, wherein the phospholipid comprises from 3 mol % to 15 mol % of the total lipid present in the particle.
8. The nucleic acid-lipid particle of claim 5, wherein the cholesterol or derivative thereof comprises from 30 mol % to 40 mol % of the total lipid present in the particle.
10. The nucleic acid-lipid particle of claim 9, wherein the PEG-lipid conjugate comprises a PEG-diacylglycerol (PEG-DAG) conjugate, a PEG-dialkyloxypropyl (PEG-DAA) conjugate, or a mixture thereof.
11. The nucleic acid-lipid particle of claim 10, wherein the PEG-DAA conjugate comprises a PEG-dimyristyloxypropyl (PEG-DMA) conjugate, a PEG-distearyloxypropyl (PEG-DSA) conjugate, or a mixture thereof.
13. The nucleic acid-lipid particle of claim 1, wherein the nucleic acid is fully encapsulated in the nucleic acid-lipid particle.
16. A method for the in vivo delivery of a nucleic acid, the method comprising: administering to a mammalian subject a nucleic acid-lipid particle of claim 1.
17. A method for treating a disease or disorder in a mammalian subject in need thereof, the method comprising: administering to the mammalian subject a therapeutically effective amount of a nucleic acid-lipid particle of claim 1.
18. The method of claim 17, wherein the disease or disorder is a viral infection.
19. The method of claim 17, wherein the disease or disorder is a liver disease or disorder.
20. The method of claim 17, wherein the disease or disorder is cancer.

Original Article:

Moderna heavily depends on Lipid Nanoparticle (LNP) technology to deliver its mRNA into target cells. LNP is a legacy tech protected by a few families of patents owned by Arbutus.

Moderna does not want to spend money licensing the tech, but rather decided to challenge the patents in a series of Inter Partes Review. Its motivation is to completely invalidate those patents or at least weaken them to gain advantage at the deal table for licensing negotiation.

On June 6th, a court hearing was held for oral arguments between lawyers of Moderna and Arbutus, in front of three USPTO judges.

Moderna submitted a third IPR challenge  earlier this year. I found this action very desperate. It is trying really hard to invalidate the patents. It is a tactic to harass Arbutus in order to distract and exhaust their resources. On the other hand, as an $ABUS shareholder, I see this as a silver lining for the distressed company. It indicates that Arbutus' LNP tech really has some value that Moderna wants badly.

Here, I summarize my understanding of Jun 6 oral arguments. It involved two patents: ‘435 and ‘127 patents.

Overall, the two parties had more arguments on ‘435 patent and less on the ‘127 patent. Let’s go over it one by one.

‘435 patent IPR argument

Round 1:

Moderna:

  1. The claimed range is too broad and overlaps with previous patent. So it is the same old stuff; nothing is new.
  2. It claimed many payloads, but only RNAi is shown with example, mRNA is claimed but no example.
  3. The language around “serum stable” and “in vivo ” “systemic delivery”, “nuclease resistence” is unclear.

Arbutus:

  1. The patent is claiming a process, not just starting materials. L054 exhibition example merely points to starting materials, “somebody already done it”. No , starting materials are not particles.
  2. Multiple constructions SNALP: Moderna is confusing in arguing multiple different constructions of particles, SNALP etc. Page 27.
  3. Serum stability:Judge: why is that a limitation of this claim?
    MR. ROSATO: Because it's hard to say that doesn't breathe life into the claim when it is defined in the specification as the invention.
  4. Overlapping ranges is not case of obviousness or routine optimalization. Components of LNP have very complicated interactions.
  5. Unexpected results has been shown by the patent. It has more than 3 data points.
  6. At that time, LNP was poorly understood, complicated, unpredictable. More cationic lipids were thought to increase toxicity and decrease efficacy.
  7. Ranges: case laws have shown overlapping ranges is not routine optimization.
  8. Payloads: Moderna and Genevant both have shown mRNA works very well.
  9. Toxicity: the petitioner claimed that ionized cationic lipids are non-toxic. DLinDMA, the very example, has been shown by petitioner in publications to be toxic.
  10. Encapsulation: Dr. Janoff has publication criticized people for calling "encapsulation" when they didn't use nuclease test. His own work on Lipoplexes are not encapsualted. They are aggreagates of lipids with nucleic acids stuck on them. Dr. Janoff agreed that these lipoplexes are not within the scope of the patent.
  11. Janoff agreed that the consensus at the time was to reduce cationic lipids.

Round 2:

Moderna:

  1. particle vs composite??? Not true, starting material is the patent.
  2. 435′ patent does not require encapsulation to be called lipid particle.
  3. People of ordinary skill can get it through routine optimization.
  4. Only one data point and there is no higher 50%+ range. How could it cover such broad coverage of nuc acids?
  5. The toxicity enough for petri dish.
  6. Drug delivery has only one case.
  7. It is important to compare to closest prior art, criticality.
  8. MRNA is different; the patent did not show.

Arbutus:

The patent is to show inceasing cationic lipids leads to low tox + high potency. And prior art expects higher tox but this claim does not.

The potency and low toxicity is across the entire range of tested formulations. The -- if you're comparing -- if you're looking at toxicity and you're comparing that to 2:30 and seeing much less -- virtually no toxicity compared to lower cationic lipid component when you're expecting higher toxicity, that's a perfectly appropriate comparison.

'127 patent IPR argument

Moderna:

  1. 95% non-lamellar morphology is inherent
  2. Method parameters may be important, but not declared in patent
  3. Everything is old.
  4. New evidence provided is irrelevant. It failed by design. The person was told by lawyer to use hand on purpose. Hand is unstable, so to fail.
  5. It is claiming same formulation and methods as 069′. ‘069 says non-lamellar. (BioEquity: not true, lying)

Arbutus:

Ground 2-4 in the initial petition request already dismissed.

Let’s look at Ground 1.

  1. To provide inherency is the burden of petitioner, but the petitioner did not show anything.
  2. The petitioner is picking and choosing from various sources. Not a legal process.
  3. '069 example is not the same, which method was used? DDM no such thing, it is a *class* of methods, hold still in real life.

Judge: Does any of those acceptable for making those particles? Does 069 make 127 particles?

Arbutus: Hindsight construction? Try without 127 in hand.

Judge: Does ‘127 tell what works what does not?

Arbutus: No. Only guidance.

Moderna:  The patent is silent on parameters.

Judge: I understand that 069 not necessarily gets the right morphology. Can you get 127 from 069?

Arbutus: No.

Summary:

For '435, it seems a motion to amend is already in discussion. So highly likely this patent will at least be amended.

For '127, there was only one argument and the answer was clear for the judge and me: You cannot get '127 from '069. '127 patent will stand intact.