Lqda v uthr final decision

[derekewhitlock]

It is also theoretically possible that the time and temperature storage components are actually critical parts of the process that must be followed.

[mcbone]

Liquidia would love to have you focus on their recent win.  But here’s a more complete story. 

UTHR’s initial patent infringement suit was filed in June of 2020 in response to Liquidia filing an NDA. Under the Hatch-Waxman act, UTHR’s patent infringement suit triggered a statutory 30-month regulatory stay on the FDA approval for Liquidia’s product, bringing the earliest approval to sometime in October of 2022. That gives UTHR a headstart in the market of maybe about 1 year if all goes well on their FDA approval for Tyvaso DPI.

UTHR initially alleged infringement of two patents, 9593066 and 9604901. UTHR later amended its complaint to allege infringement of a third patent, 10716793. The case is pending in the District Court of Delaware.

Now, as is the right of an accused patent infringer after being sued in district court, Liquidia filed what are referred to as inter partes reviews (IPR’s) at the Patent and Trademark Office (PTO) for the three patents. This is a parallel forum to the Delaware district court. If Liquidia knocks out any of the claims of any of the patents in the IPR’s, UTHR will not be able to pursue those claims in district court, although it could appeal to the Federal Circuit Court of Appeals.

So far, the PTO has denied Liquidia’s request to institute an IPR for the ‘066 patent. See here: www.globenewswire.com/en/news-release/2020/10/14/2108510/0/en/Liquidia-Provides-Update-on-U-S-Patent-Trial-and-Appeal-Board-Decision-on-Inter-Partes-Review-of-Two-United-Therapeutics-Tyvaso-Patents.html Liquidia will have to defend itself in the Delaware district court for ‘066, which is way more expensive than an IPR, which itself is expensive. Here’s the ‘066 patent if you’re interested: patentimages.storage.googleapis.com/5b/a9/f7/6217011b1c00a2/US9593066.pdf

Yes, Liquidia knocked out all but two of the claims of '901, at least for now. We don’t know if UTHR will appeal the PTO decision.

I don’t know the status of the IPR of ‘793. But, unlike the other two patents, one of the inventors on ‘793 is Dr. Robert Roscigno, who is now Senior Vice President of Product Development at Liquidia. UTHR has argued that Liquidia is barred from even contesting the validity of ‘793 due to a legal doctrine known as “assignor estoppel.” Under this doctrine, an assignor (Roscigno assigned his rights to UTHR when he still worked at UTHR) is barred from attacking the patent's validity in subsequent patent infringement litigation. This issue can arise when one of the inventors on a patent assigns the patent-in-suit to his/her current employer and thereafter goes to work for the competition, as has happened here. UTHR went for a “knockout punch” on this issue but did not succeed. See here: www.ded.uscourts.gov/sites/ded/files/opinions/20-755.pdf Nevertheless, it’s fact sensitive, and it will be expensive for Liquidia to defend.

Then there’s the trade secret allegations. See here: www.biospace.com/article/united-therapeutics-continues-suit-against-liquidia-this-time-for-trade-secret-misappropriation/
UTHR’s lawyers will argue that that Dr. Roscigno had access to secret information while he worked at UTHR and he has now run off with it, trying to use it at Liquidia. More expensive litigation.

Incidentally, all three of these patents date back to 2006 or 2007, long before UTHR and MNKD hooked up for Tyvaso DPI. The ‘793 patent, however, clearly covers inhaling a dry powder form of Tyvaso, as well as mists, nebulizers, etc. See claims 2-7. patentimages.storage.googleapis.com/b2/3e/fb/109f2d655b95ff/US10716793.pdf

Don’t be misled by Liquidia’s press releases. This is a big expensive fight and nowhere near over. And we all know who’s the 800 lb. gorilla.

[mango]

Trade secret theft is a federal crime. You can look up the cases on the Dept of Justice website, they make PRs of them.

Point is, this is not smoke and mirrors by UT, this is very serious allegations of criminal activity, of which UT alleges to have evidence of.

The settlement could range from $0-hundreds of millions.

I would be very worried if I were a Liquidia investor.

[myocat]

Bought some at 2.70.

[mymann]

Huge gains for lqda today. Must be good news about the court ruling favorable to lqda.

[myocat]

LQDA PDUFA NOV 11 is another play date....

[mango]

I was doing some digging into Liquidia’s Treprostinil DPI ingredients via their patents and I found them listed in the claims of their most recent granted patent:

5. The method of claim 1, wherein the dry powder composition comprises molded dry particles comprising by percent solids about 0.581 percent treprostinil sodium, about 92.32 percent trehalose, about 2.19 percent polysorbate 80, about 4.39 percent L-leucine, about 0.26 percent sodium citrate, and about 0.25 percent sodium chloride.

patents.justia.com/patent/10898494#claims



Trehalose a major ingredient in Liquidia’s Treprostinil DPI making up over 92% of the formulation

From a recent news article

"In 2000, trehalose was approved as a food additive in the United States for a number of foods from sushi and vegetables to ice cream," says one of the researchers, Robert Britton from the Baylor College of Medicine in Texas.

In this case, trehalose is being linked with the rise of two strains of the bacterium Clostridium difficile, capable of causing diarrhea, colitis, organ failure, and even death.

www.sciencealert.com/common-superbug-fuelled-by-popular-sugar-additive-trehalose


From a publication in Nature

Dietary trehalose enhances virulence of epidemic Clostridium difficile

“We propose that the implementation of trehalose as a food additive into the human diet, shortly before the emergence of these two epidemic lineages, helped select for their emergence and contributed to hypervirulence.”

www.nature.com/articles/nature25178



L-Leucine is an ingredient in Liquidia’s Treprostinil DPI

Very high doses of leucine may cause low blood sugar (hypoglycemia). It may also cause pellagra. Symptoms of this can include skin lesions, hair loss, and gastrointestinal problems.

www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid=19&contentid=Leucine

[sweedee79]

Oct 12, 2021 12:02:21 GMT -5 mango said:

I was doing some digging into Liquidia’s Treprostinil DPI ingredients via their patents and I found them listed in the claims of their most recent granted patent:

5. The method of claim 1, wherein the dry powder composition comprises molded dry particles comprising by percent solids about 0.581 percent treprostinil sodium, about 92.32 percent trehalose, about 2.19 percent polysorbate 80, about 4.39 percent L-leucine, about 0.26 percent sodium citrate, and about 0.25 percent sodium chloride.

patents.justia.com/patent/10898494#claims



Trehalose a major ingredient in Liquidia’s Treprostinil DPI making up over 92% of the formulation

From a recent news article

"In 2000, trehalose was approved as a food additive in the United States for a number of foods from sushi and vegetables to ice cream," says one of the researchers, Robert Britton from the Baylor College of Medicine in Texas.

In this case, trehalose is being linked with the rise of two strains of the bacterium Clostridium difficile, capable of causing diarrhea, colitis, organ failure, and even death.

www.sciencealert.com/common-superbug-fuelled-by-popular-sugar-additive-trehalose


From a publication in Nature

Dietary trehalose enhances virulence of epidemic Clostridium difficile

“We propose that the implementation of trehalose as a food additive into the human diet, shortly before the emergence of these two epidemic lineages, helped select for their emergence and contributed to hypervirulence.”

www.nature.com/articles/nature25178



L-Leucine is an ingredient in Liquidia’s Treprostinil DPI

Very high doses of leucine may cause low blood sugar (hypoglycemia). It may also cause pellagra. Symptoms of this can include skin lesions, hair loss, and gastrointestinal problems.

www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid=19&contentid=Leucine

mango, what were they talking about on the lqda board yesterday? Something about dosing... They were saying that the FDA has reduced our dosages on the label due to the Afrezza black box warning? Does this have anything to do with the citizen petition? 

[mango]

Oct 12, 2021 12:41:49 GMT -5 sweedee79 said:

Oct 12, 2021 12:02:21 GMT -5 mango said:

I was doing some digging into Liquidia’s Treprostinil DPI ingredients via their patents and I found them listed in the claims of their most recent granted patent:

5. The method of claim 1, wherein the dry powder composition comprises molded dry particles comprising by percent solids about 0.581 percent treprostinil sodium, about 92.32 percent trehalose, about 2.19 percent polysorbate 80, about 4.39 percent L-leucine, about 0.26 percent sodium citrate, and about 0.25 percent sodium chloride.

patents.justia.com/patent/10898494#claims



Trehalose a major ingredient in Liquidia’s Treprostinil DPI making up over 92% of the formulation

From a recent news article

"In 2000, trehalose was approved as a food additive in the United States for a number of foods from sushi and vegetables to ice cream," says one of the researchers, Robert Britton from the Baylor College of Medicine in Texas.

In this case, trehalose is being linked with the rise of two strains of the bacterium Clostridium difficile, capable of causing diarrhea, colitis, organ failure, and even death.

www.sciencealert.com/common-superbug-fuelled-by-popular-sugar-additive-trehalose


From a publication in Nature

Dietary trehalose enhances virulence of epidemic Clostridium difficile

“We propose that the implementation of trehalose as a food additive into the human diet, shortly before the emergence of these two epidemic lineages, helped select for their emergence and contributed to hypervirulence.”

www.nature.com/articles/nature25178



L-Leucine is an ingredient in Liquidia’s Treprostinil DPI

Very high doses of leucine may cause low blood sugar (hypoglycemia). It may also cause pellagra. Symptoms of this can include skin lesions, hair loss, and gastrointestinal problems.

www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid=19&contentid=Leucine

mango , what were they talking about on the lqda board yesterday? Something about dosing... They were saying that the FDA has reduced our dosages on the label due to the Afrezza black box warning? Does this have anything to do with the citizen petition? 

I don’t know anything about that…Can you post a link to it? 

[harryx1]

sweedee79 The dosing was pertaining to the studies done by LQDA and UTHR - Gregonious thinks that LIQ861 is superior to Tyvaso DPI because their study dosed up to 220 mcg.  MNKD's phase 1 dosed up to 150 mcg but UTHR decided to do the BREEZE study with 32, 48 & 64 mcg  -  I don't think it matters as much and believe that 64 mcg of nebulized Tyvaso does not equal 64 mcg of Tyvas DPI where the latter is more powerful as more gets into the lung and further deep into the lung. RLS showed that with the results of RLS103 delivered 7-fold greater than a nebulizer.

Further more MNKD has spent millions and years of studies on FDKP. At the minimum LQDA should have to do equivalent studies on Trehalose which I believe they have not done.

I personally would not want a sugar sitting in my lungs and would rather a salt that only stays ~1 hour half life, is inhert and excreted by the body unchanged.

[mango]

I just read Gregonious’ post about that. It’s all speculation and FUD. He’s peddling the FDA will slap a Black Box Warning on TreT for the same thing as Afrezza. Won’t happen. Our dosage is fine.

[sweedee79]

Good... Thanks you guys.. I was worried we might have another label issue

[celo]

Isn't the dosing argument mute if all the patients prospered on Tyvaso DPI? What ever dose was given seemed to do great.

[Clement]

Oct 12, 2021 13:11:20 GMT -5 harryx1 said:

sweedee79 The dosing was pertaining to the studies done by LQDA and UTHR - Gregonious thinks that LIQ861 is superior to Tyvaso DPI because their study dosed up to 220 mcg.  MNKD's phase 1 dosed up to 150 mcg but UTHR decided to do the BREEZE study with 32, 48 & 64 mcg  -  I don't think it matters as much and believe that 64 mcg of nebulized Tyvaso does not equal 64 mcg of Tyvas DPI where the latter is more powerful as more gets into the lung and further deep into the lung. RLS showed that with the results of RLS103 delivered 7-fold greater than a nebulizer.

Further more MNKD has spent millions and years of studies on FDKP. At the minimum LQDA should have to do equivalent studies on Trehalose which I believe they have not done.

I personally would not want a sugar sitting in my lungs and would rather a salt that only stays ~1 hour half life, is inhert and excreted by the body unchanged.

Remember when we called Treprostinil Technosphere "TreT" and Mannkind did the phase one trial.  The following is from June 11, 2018:
pulmonaryhypertensionnews.com/2018/06/11/treprostinil-delivered-using-technosphere-portable-inhaler-seen-as-safe-in-phase-1-trial/

"A Phase 1 clinical trial (NCT03464864) found that treprostinil can be safely delivered at varying doses using Technosphere, a novel inhalation device, MannKind, the device’s developer, announced.

Treprostinil — a vasodilator — was approved by the U.S. Food and Drug Administration (FDA) in 2002 for the treatment of pulmonary arterial hypertension (PAH). The drug is commercially available as Tyvaso, Orenitram, and Remodulin.

Treprostinil-Technosphere (TreT) is designed to deliver the active ingredient, treprostinil, via a small, novel, portable breath-powered inhaler. The goal is to simplify dosing, and offer PAH patients a more convenient and tolerable treprostinil treatment option.

The trial enrolled 48 healthy individuals, who each received a single dose of Treprostinil inhalation powder daily. The objective was to establish the maximum tolerated dose in these healthy volunteers, starting at 30 mcg and going up to 300 mcg (doses tested: 30, 60, 90, 120, 150, 180, 240, and 300 mcg).

Blood samples were collected from each patient to determine treatment concentrations and pharmacokinetics — the study of the time from drug absorption, distribution, and metabolism to its excretion from the body.

Results showed that progressive dosing of TreT significantly exceeded blood concentration and exposure levels of the maximum recommended dose of Tyvaso (inhaled treprostinil; current standard of care) without causing severe adverse events."

[Clement]

Mannkind dosed up to 300mcg in the phase one trial. No servere adverse events.