A market analyst report just published speculates that Mylan Inc. may be in a position to market Generic Oracea as soon as the first quarter of 2011. These speculations are based on the successful outcome of a trial set down for December 2010 where Mylan will argue against the 5 patents that Galderma holds for the intellectual property associated with Oracea.

Rosacea News covered Galderma’s legal proceedings against Mylan in March 2009. Mylan has filed an Abbreviated New Drug Application (ANDA) for Doxycycline Delayed-release (DR) Capsules USP, 40 mg. This filing was challenged in court by Galderma.

Today’s article is an opinion piece attributed to Needham & Company and published at StreetInsider.com, suggesting that if Mylan is successful in their ANDA application, their share price would rise based on their access to the $240m a year Oracea market.

Needham & Company Maintains a ‘Strong Buy’ on Mylan (MYL); Receives Final Approval for Generic Oracea Potentially Setting Up Exclusivity Launch

July 13, 2010 7:29 AM EDT

Needham & Company maintains a ‘Strong Buy’ rating on Mylan Inc. (NYSE:MYL), price target $26.

Needham analyst says, “MYL has received final FDA approval for generic Oracea, a $240.0MM oral formulation of doxycycline marketed by Galderma for the treatment of rosacea.

MYL is first-to-file on Oracea though despite the final approval, immediate launch is precluded per a preliminary injunction granted innovator Galderma tied to litigation on five Orange Book listed patents. With trial scheduled for early December 2010, launch potential appears unlikely before late 1Q11 at the earliest.

We are certain MYL has 180-day statutory exclusivity though less certain the company is alone given possibility second-filer Lupin also filed its ANDA before Galderma listed patents in the Orange Book and certified simultaneously with MYL.

Impax Labs (Nasdaq: IPXL) (Hold-rated) has also filed and was subject to a 30-month stay ending Feb. 2012.”

Some other interesting points suggested by the article

• Mylan was the first to file to be granted permission for generic Oracea.
• Lupin and Impax Labs have also filed to have permission to sell generic Oracea.

Whilst all of this is highly speculative, and it is the job of market analysts to offer their opinions based on predicting the future, it is still interesting to see that the market for rosacea treatments is large enough to be fought over.

Rosacea sufferers would benefit from the availability of cheap generic delayed release doxycycline 40mg, and paradoxically also benefit when Galderma earns income from sales of branded Oracea: through the availability of generated R&D dollars.

What do you think ?

Are you being held back by the price of Oracea ? Are you waiting for generic Oracea ?

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How to best optimize laser and IPL treatments has long been debated. Should the rosacean deliberately engineer a flush prior to treatment? Should anti-inflammatories or anti-hypertensives be taken after treatment? Of course, many have long since reached their own (perhaps tentative) conclusions and employed diverse means to prompt pre-treatment flushing and soothe post-treatment inflammation.

Yet, if sufferers have been quick off the mark, the givers of treatment – with a few laudable exceptions – and the makers of drugs, have been characteristically slow to catch on: too complacent to investigate and too un-enterprising to experiment.

The news that a bunch of presumably  bright people have decided to plough considerable resources into the development of a product comprising a topical vasodilator for pre-treatment, a topical vasoconstrictor for post-treatment, and a set of instructions on how and when to apply both, might just indicate that definitive answers to these questions are around the corner.

Control of Blood Vessel Physiology to Treat Skin Disorders

In a method for treating an affected skin region of a patient having a skin disorder, a vasodilation composition is applied to an affected skin region of a patient, the affected skin region exhibiting a skin disorder characterized by at least one abnormal blood vessel, and the affected skin region is then treated so as to non-invasively disrupt tissue architecture, e.g., by inducing ischemia, of the at least one abnormal blood vessel.

A vasoconstriction composition can then be applied to the skin region to cause vasoconstriction of the at least one blood vessel in order to promote healing.

[Full PDF]

Biochemics’ rationale for the use of the vasodilator is that it makes vessels easier to target and more susceptible to irreversible damage. The vasoconstrictor is applied to render vessel collapse and shrinkage more likely. Biochemics are collaborating with the laser manufacturer Cynosure and they have already conducted a trial of sorts.

The patent application is unusually readable and not without additional interest. For those who can’t be bothered but whose eyes lit up at the mention of vasoconstrictors, the constricting substances mentioned are: phytonin, phenyl-epinephrine, caffeine, arnica extract, cypress extract, Solomon’s seal extract, nymphaea alba flower extract, butcher’s broom extract, grapefruit oil, pomegranate and bugleweed extract.

Disclaimer: Apparently, it’s a lifetime’s work to formulate a vasoconstrictor that doesn’t cause rebound dilation, so, if you are minded to hunt any of these down, proceed with caution.

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A newly filed patent contains a proposed rosacea treatment using small bands of infrared radiation between 790nm and 900nm with a power between 1 and 100 mW/cm^2. The unit proposed could be a LED device, used from twice a day to every 10 days. An energy density between 3 and 180 Joules/cm^2 is proposed.

Infrared Light is in the invisible spectrum below red, with wavelengths from 700nm to 2,000nm. We know that infrared light penetrates skin tissue more effectively than visible light.

An example device described is the OMNILUX Plus, which is promoted as “(Infra-red) works as a combination therapy with the Revive (red) head for even better skin rejuvenation, ideal for deeper lines and wrinkles”. OMNILUX Plus is based on a matrix of Infra Red LEDs, which provide narrowband 830nm light. This device is not currently promoted as a treatment for rosacea, so it seems that this patent covers using an existing treatment method for a new condition – rosacea.

The example treatment regime used an OMNILUX Plus unit at 830nm (+/- 0.5nm), using 55 mW/cm^2 at a distance of 1-10cm from the skin for 20 minutes with a power of 66 Joules/cm^2, twice a week for four weeks. Goggles were used and the unit was further placed 3-5cm from the patient’s nose.

The patent says that the patient enjoyed substantially reduced telangiectasia and reduced inflammatory papules.

Treating erythematotelangiectatic rosacea or papulopustular rosacea with narrow-band infrared light radiation and radiation kits therefor

United States Patent Application 20090270847, Lee; Seung Yoon, October 29, 2009

A method of treating erythematotelangiectatic rosacea or papulopustular rosacea in a subject comprises exposing the subject’s skin in need thereof to narrow-band infrared radiation at a wavelength(s) in a range of between 790 nm and 900 nm and having a band width of between 0 nm and 20 nm, in an effective dose to treat erythematotelangiectatic rosacea or papulopustular rosacea and essentially not to cause photothermolysis of the skin. Alternatively, a method of treating erythematotelangiectatic rosacea or papulopustular rosacea in a subject comprises exposing the subject’s skin in need thereof to narrow-band infrared radiation at a wavelength(s) in a range of between 790 nm and 900 nm and having a band width of between 0.1 nm and 20 nm, in an effective dose to treat erythematotelangiectatic rosacea or papulopustular rosacea. A kit for such methods comprises a radiation source generating narrow-band infrared radiation at a wavelength(s) in a range of between 790 nm and 900 nm, the narrow-band infrared radiation having a band width of between 0 nm and 20 nm and having a power density of between 1 mW/cm^2 and 100 mW/cm^2, and a manual instructing a user how to use the narrow-band infrared radiation for treating erythematotelangiectatic rosacea or papulopustular rosacea.

Featured Product

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This is a challenge to the patents held by Galderma, relating to the Oracea product.

In March we also read that Galderma was suing Mylan Pharmaceuticals, also over alleged Oracea patent infringements.

The announcement of this second ANDA:Generics challenge to Oracea can only be seen as good news for rosacea sufferers. If Oracea was available as a generic drug it would  immediately become more affordable and thus accessible to rosacea sufferers.

Abbreviated New Drug Application (ANDA): Generics

An Abbreviated New Drug Application (ANDA) contains data which when submitted to FDA’s Center for Drug Evaluation and Research, Office of Generic Drugs, provides for the review and ultimate approval of a generic drug product. Once approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, low cost alternative to the American public.

The FDA can also grant Galderma an extra 5 years on top of the regular patent period, so the battle over Generic Oracea could indeed last a long time.

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For me the sun has always been my worst trigger. Certainly physical sunscreens such as those based on zinc oxide have been immensely helpful to me. Having another option of a gentle sunscreen sounds like a win for all rosacea sufferers.

This patent application is proposing a sunscreen that is not waterproof, so would need to be re-applied regularly. The patent application, which actually reads in part like a product announcement, suggests that in dry conditions protection will be effective for about 2 hours per application of this proposed product.

Composition of a Water-Soluble Sunscreen Preparation for Acne Rosacea, 20090202460, Nieuwenhuijsen; Bart.

The object of the invention is to provide a topical preparation for (acne) rosacea and other sensitive skin types that protects the face from harmful UV rays without the use of chemical sunscreen ingredients. It has long been found that chemical sunscreen ingredients (most popular are oxybenzone and avobenzone) can cause an increase of rosacea symptoms (flushing, erythema, papules) (Nedorost (2003) and Landers et al., 2003). Furthermore, typical waterproof sunscreen preparations also contain various forms of silicones that are used to increase the hydrophobicity of the sunscreen. These waterproof sunscreen preparations impair the release of heat from the skin. The combination of this "trapped heat" and a sensitivity to chemical sunscreen ingredients, is harmful to rosacea skin. Therefore, a sunscreen preparation that is water-soluble and uses alternative UV absorbing and UV scattering ingredients would be very useful in protecting rosacea skin from harmful UV rays.

Claim 1) describes the formulation, including an extract from a woody climbing shrub native to west and central Africa known as Griffonia simplicifolia. The amino acid 5-HTP is one of the building blocks to the neurotransmitter serotonin. Histidine and N-AcetyL-Tyrosine are also amino acids.

1) … The formulation is comprised of titanium dioxide to reflect harmful UV rays and a blend of UV absorbing amino acids, 5-Hydroxy-Tryptophan (from Griffonia simplicifolia extract), Histidine and N-AcetyL-Tyrosine in a gel base.

The Griffonia simplicifolia extract is slightly brown in color, which can offset the white appearance of the Titanium Dioxide.

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One of inventors of this patent is well known to rosacea sufferers. Dr. Mark Mannis has been friendly and helpful to online rosacea sufferers, see his interview – Ocular Rosacea: Dr. Mark J. Mannis, MD. He has also been mentioned in Rosacea News in the past; wearing contact lenses and ocular rosacea and was a contributor to the standard classification of rosacea.

Rosacea News first highlighted a possible diagnostic test for ocular rosacea in late 2005. The journal article from the Journal of Proteome Research concluded that “The high abundance of oligosaccharides in the tear fluid of patients with rosacea may lead to an objective diagnostic marker for the disease.”

An objective diagnostic test for ocular rosacea would be an excellent achievement for rosacea sufferers. Being able to be definitively diagnosed with ocular rosacea, especially if no other other rosacea symptoms are present, will enable those sufferers to seek immediate treatment. As we all know an accurate diagnosis is almost the most important step in getting better.

United States Patent Application 20090118141, May 7, 2009. METHODS OF OLIGOSACCHARIDE PROFILING FOR THE DETECTION OF OCULAR ROSACEA, Lebrilla; Carlito B.; (Davis, CA) ; An; Hyunjoo; (Davis, CA) ; Alvarenga; Lenio S.; (Sao Paulo, BR) ; Mannis; Mark D.; (Carmichael, CA)

The present invention provides methods for identifying oligosaccharides specific to an inflammatory or infectious disease, methods for diagnosing an inflammatory or infectious disease by detecting the presence or absence of such oligosaccharides, and methods for treating an inflammatory or infectious disease by administering antibodies directed to such oligosaccharides. The present invention also provides methods for diagnosing ocular rosacea by determining the presence or absence of specific oligosaccharide markers. In addition, the present invention provides markers for ocular rosacea comprising 0-linked oligosaccharides as well as kits for diagnosing or treating ocular rosacea.

The patent raises the possibility of an ocular rosacea treatment that uses “a therapeutically effective amount of an antibody that binds specifically to a unique oligosaccharide”. This suggests that a new class of rosacea treatments might arise from this invention.

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Methods of treating acne and rosacea with electrochemically generated zinc ions:

The present invention features a method of treating acne or rosacea by applying to the skin electrochemically generated zinc ions. In one embodiment, the method includes topically applying a device including an anode containing zinc.

Methods of treating acne and rosacea with galvanic generated electricity

The present invention features a method of treating acne or rosacea on the skin by applying electricity to skin in need of such treatment wherein said electricity is generated by a first conductive electrode in electric communication with a second conductive electrode, wherein both the first conductive electrode and the second conductive electrode are in ionic communication with the skin, wherein the difference of the standard potentials of the first conductive electrode and the second conductive electrode is at least 0.2 V and wherein the electrons that pass between the first conductive electrode and the second conductive electrode are generated as a result of such difference of the standard potentials.

There is also an exhaustive list of possible alternative active agents “retinoids such as tretinoin, isotretinoin, motretinide, adapalene, tazarotene, azelaic acid, and retinol; salicylic acid; benzoyl peroxide; resorcinol; sulfur; sulfacetamide; urea; antibiotics such as tetracycline, metronidazole, and erythromycin; anti- inflammatory agents such as corticosteroids (e.g., hydrocor- tisone), ibuprofen, naproxen, and hetprofen; and imidazoles such as ketoconazole and elubiol; and salts, esters, and other derivatives thereof. Other examples of anti-acne active agents include essential oils, alpha-bisabolol, dipotassium glycyrrhizinate, camphor, (3-glucan, allantoin, feverfew, flavonoids such as soy isoflavones, saw palmetto, chelating agents such as EDTA, lipase inhibitors such as silver and copper ions, hydrolyzed vegetable proteins, inorganic ions of chloride, iodide, fluoride, and their nonionic derivatives chlorine, iodine, fluorine, and other valences, synthetic phospholipids and natural phospholipids such as Arlasilk phospholipids COM, SV, EFA, PLN, and GLA”.

Continuing, that patent also covers the usage of antifungals, antibiotics, antimicrobials, antispsoriatics, anti-inflammatories etc. A LED might included to illuminate the skin, modulate the current, show it is operating as well as provide some low level light therapy.

The science of using an electric charge to cross the skin barrier is called iontopheresis. For some active ingredients, being unable to cross the skin barrier can restrict its effectiveness or require formulations that use other molecules to assists the active molecules through the outer skin barrier. As part of the research into flushing and emotional responses I was connected to a probe with a small electric current applied, and the blood flow measured. As more current was applied the pain increased, I do hope that this proposed treatment is painless.

doing my bit for rosacea research; Perth wake up !

In the first part of the test a chemical called acetylcholine is put on to the skin underneath the probe. According to wikipedia, acetylcholine is one of the first neurotransmitters discovered. A small electric current is applied in short bursts to help the acetylcholine breach the skin barrier. At various points you are asked to assess to amount of pain and stinging you feel. The worst I felt was unpleasant but not untolerable.

The point is to measure the increased blood flow and also the amount of discomfort felt. If differences between rosacea sufferers and non-rosacea sufferers can be proved then that would be a good result.

The patent mentions a `wearable patch or facial mask type adhesive device’ perhaps giving a clue to what the product might look like. The carrier may be `immobilized within an absorbent material such as gauze or non-woven pad’.

Of course just because something is patented doesn’t mean that it 1) works or 2) will become a product, but may still provide insights into what the future holds.

As the patents are owned by Johnson & Johnson I wonder if we ever might see these sorts of devices available to the mass market ?

State University of New York, Galderma Sue Mylan

March 20 (Bloomberg) — The State University of New York, Galderma Laboratories LP and New York University sued generic- drug maker Mylan Pharmaceuticals Inc. for allegedly infringing four patents for the drug Oracea, used to treat skin blemishes.

…

“Mylan was aware of the existence” of the patents, and the patent-holders “will be irreparably harmed” unless stopped by a judge, the plaintiffs said in a complaint filed yesterday in federal court in Wilmington, Delaware.

The Bloomberg release specifically mentions the following patents:

• 7,211,267: Methods of treating acne
• 7,232,572: A method of treating rosacea in a human in need thereof comprising administering to said human a tetracycline compound in an amount that is effective to treat rosacea, but has substantially no antibiotic activity.
• 5,919,775: Method for inhibiting expression of inducible nitric oxide synthase with tetracycline
• 5,789,395: Method of using tetracycline compounds for inhibition of endogenous nitric oxide production

We also know that Collagenex holds up to 6 patents relating to Oracea. One of these patents, which was highlighted by Rosacea News in May 2006, covers treating ocular and facial rosacea at the same time with one treatment.

The market for rosacea treatments is certainly worth fighting for. The current value of rosacea prescriptions is greater than $500m a year. Galderma is well positioned to take advantage of this market, and the even bigger dermatology market with their rosacea products such as Metrogel, Oracea, the upcoming Sansrosa as well as the Cetaphil range.

Update: some more information has surfaced on the details of the claim

SUNY, NYU, Galderma Sue Generics Firm Mylan for Allegedly Infringing Rosacea Rx IP

The suit alleges that Mylan Pharmaceuticals, a business unit of Mylan Laboratories, recently filed an abbreviated new drug application with the US Food and Drug Administration for a generic doxycycline delayed-release capsule.

Though the date of the filing is not clear, the plaintiffs received notification of Mylan’s ANDA on or about Feb. 4 of this year, and said that Mylan claimed in its ANDA that specific claims of the four patents were invalid and would not be infringed by manufacture or sale of the generic product.

Consequently, SUNY, NYU, and Galderma filed their suit, claiming that Mylan’s ANDA filing and allegations within that filing constituted infringement of the patents; and that they would be irreparably harmed if Mylan were allowed to manufacture or sell the generic product. Moreover, the plaintiffs alleged in their complaint that Mylan’s actions are "an exceptional case … because Mylan was aware of the existence of the [patents] at the time of the submission of [the] ANDA."

…

The oldest of the four patents, No. ’395, was filed on Aug. 30, 1996, and thus would be set to expire on Aug. 30, 2016; while the youngest, No. ’267, was filed on Feb. 18, 2005, and thus would expire on Feb. 18, 2025, barring any extensions.

… according to Collagenex’s 2007 financial results, released in March of last year just before the Galderma acquisition closed, Oracea had $52.5 million in net sales in 2007.

And some interesting snippets from Mylan Confirms Four First-to-File Challenges

Mylan Pharmaceuticals was sued by Galderma Laboratories Inc., Galderma Laboratories LP, The Research Foundation of the State University of New York and New York University in the U.S. District Court of Delaware in connection with the ANDA filing for Doxycycline Delayed-release (DR) Capsules USP, 40 mg.

Doxycycline DR Capsules are the generic version of Galderma’s adult rosacea treatment Oracea Capsules, which had approximately $82 million in U.S. sales for the twelve months ending Dec. 31, 2008, according to IMS Health

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Those following the development of sansrosa closely will be encouraged by this patent application; making this new treatment seem one step closer to being available.

Brimonidine Compositions for Treating Erythema, United States Patent Application 20090061020

The present invention is directed to a pharmaceutical composition including brimonidine tartrate in an amount from about 0.17 percent by weight to about 0.19 percent by weight in a pharmaceutically acceptable carrier such as a gel or cream. The invention also relates to a method of treating erythema in a patient with rosacea by administering the composition of the invention to the site of erythema on the skin of the patient.

More extracts:

A composition wherein the gel comprises water, a gelling agent, a skin-penetrating agent (propylene glycol), a moisturizer (glycerin), a preservative (methylparaben or phenoxyethanol), a gelling agent (Carbomer 934P), a protective agent (titanium dioxide), a carrier to have a pH of about 5 to about 7.5 (sodium or potassium hydroxide)

A composition wherein the gel comprises water, a carbomer, propylene glycol, glycerin, methylparaben, phenoxyethanol, glycerin, titanium dioxide and a sufficient amount of base to cause the carrier to have a minimum pH of about 6.2 and a maximum pH of about 6.8 when the gel is diluted by a factor of ten.

Later on we can see the relative amounts of each component.

Gel Formulation

The Phase 2 studies used a composition similar to the above gel formulation. Three strengths were used for the trials – 0.02%, 0.07% and 0.20% brimonidine tartrate. The placebo of course contained no brimonidine tartrate. A strong benefit in reduction of erythema was seen in the mid and high doses.

Cream Formulation

Dosage

We can also see that `Typically, one to four applications per day are recommended during the term of treatment.’

Do you see anything you don’t like ? Anything interesting or of concern given your own experience with topicals ?

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ADMINISTRATION OF TROPISETRON FOR TREATING INFLAMMATORY SKIN DISEASES/DISORDERS, United States Patent Application 20090048289.

Tropisetron or salt thereof, formulated into diverse pharmaceutical/dermatological compositions, is useful for the treatment of a variety of inflammatory skin disorders/diseases, e.g., eczema, psoriasis, rosacea, acne vulgaris, ulcers, seborrhoeic dermatitis and irritations induced by chemical, physical or mechanical agents, notably rosacea.

Tropisetron has been approved in the past in palliative therapy to prevent or treat chemotherapy induced nausea and vomiting and to treat post-operative nausea and vomiting. Tropisetron is not available in the United States.

Tropisetron has been found effective in treating rheumatic arthritis, IBS, diarrhoea, central nervous system related disorders like anxiety, drug addiction, cognitive functions, myofascial pain, chronic fatigue syndrome, fibromyalgia and certain forms of pruritus.

Further, Claim 8 in the patent application is interesting;  “there is, however, no published data regarding the use of tropisetron in order to treat an inflammatory skin disorder/disease and preferably rosacea”. If indeed Galderma have found this agent to be effective in treating rosacea, they may well end up owning the patent outright.

The claims proposed in the patent embody a topical agent being a gel, cream or lotion with a concentration from 0.0001% to 20%. The claims also mention topical application to the eye and cover oral and sub cutaneous preparations as well.

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