What happens when lifestyle drugs like Viagra and Cialis lose patent protections

The first patent for Viagra was filed in May 1994and was issued in 2002, but Viagra did not begin as an ED pill. The compound was originally developed and patented as a drug called Revatio to treat high blood pressure (hypertension) and chest pain due to heart disease (angina pectoris), but clinical trials showed that it was more effective at inducing erections than anything else.

US20080009502A1 – Tadalafil solid composites – Google Patents

Publication number US20080009502A1 US20080009502A1 US11/595,481 US59548106A US2008009502A1 US 20080009502 A1 US20080009502 A1 US 20080009502A1 US 59548106 A US59548106 A US 59548106A US 2008009502 A1 US2008009502 A1 US 2008009502A1 Authority US United States Prior art keywords tadalafil carrier solid composite solid solution Prior art date 2006-07-07 Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.) Abandoned Application number US11/595,481 Inventor Ilan Zalit Boaz Pal Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.) Access Business Group International LLC Teva Pharmaceuticals USA Inc Original Assignee Access Business Group International LLC Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.) 2006-07-07 Filing date 2006-11-09 Publication date 2008-01-10 2006-07-07 Priority to US81921506P priority Critical 2006-11-09 Application filed by Access Business Group International LLC filed Critical Access Business Group International LLC 2006-11-09 Priority to US11/595,481 priority patent/US20080009502A1/en 2007-04-02 Assigned to TEVA PHARMACEUTICALS USA, INC. reassignment TEVA PHARMACEUTICALS USA, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: TEVA PHARMACEUTICAL INDUSTRIES LTD. 2007-04-02 Assigned to TEVA PHARMACEUTICAL INDUSTRIES LTD. reassignment TEVA PHARMACEUTICAL INDUSTRIES LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PAL, BOAZ, ZALIT, ILAN 2008-01-10 Publication of US20080009502A1 publication Critical patent/US20080009502A1/en Status Abandoned legal-status Critical Current

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Classifications

• • A — HUMAN NECESSITIES
  • A61 — MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K — PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
  • A61K47/00 — Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50 — Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A — HUMAN NECESSITIES
  • A61 — MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K — PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
  • A61K9/00 — Medicinal preparations characterised by special physical form
  • A61K9/08 — Solutions
  • A — HUMAN NECESSITIES
  • A61 — MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K — PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
  • A61K31/00 — Medicinal preparations containing organic active ingredients
  • A61K31/33 — Heterocyclic compounds
  • A61K31/395 — Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495 — Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4985 — Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
  • A — HUMAN NECESSITIES
  • A61 — MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K — PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
  • A61K47/00 — Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06 — Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08 — Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10 — Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
  • A — HUMAN NECESSITIES
  • A61 — MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K — PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
  • A61K47/00 — Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30 — Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/32 — Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
  • A — HUMAN NECESSITIES
  • A61 — MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K — PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
  • A61K47/00 — Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30 — Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/34 — Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
  • A — HUMAN NECESSITIES
  • A61 — MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K — PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
  • A61K47/00 — Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30 — Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36 — Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38 — Cellulose; Derivatives thereof
  • A — HUMAN NECESSITIES
  • A61 — MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P — SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00 — Drugs for genital or sexual disorders; Contraceptives
  • A61P15/10 — Drugs for genital or sexual disorders; Contraceptives for impotence
  • A — HUMAN NECESSITIES
  • A61 — MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P — SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00 — Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
  • A — HUMAN NECESSITIES
  • A61 — MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P — SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00 — Drugs for disorders of the cardiovascular system
  • A61P9/08 — Vasodilators for multiple indications

  Abstract

  This invention relates to oral pharmaceutical compositions suitable for making pharmaceutical formulations for oral administration that provide for the rapid dissolution of the phosphodiesterase 5 inhibitor tadalafil. In particular, the pharmaceutical compositions comprise solid composites of tadalafil exhibiting high solubility and rate of dissolution. The invention further relates to methods of preparing these pharmaceutical formulations and the use of such pharmaceutical formulations for treating diseases associated with PDE5 inhibitors.

  Description

  This application claims the benefit of U.S. Provisional Application No. 60/819,215, filed Jul. 7, 2006, the contents of which are herein incorporated by reference.

  This invention relates to oral pharmaceutical compositions suitable for making pharmaceutical formulations for oral administration that provide for the rapid dissolution of the phosphodiesterase 5 inhibitor tadalafil. In particular, the pharmaceutical compositions comprise solid composites of tadalafil exhibiting high solubility and rate of dissolution. The invention further relates to methods of preparing these pharmaceutical formulations and the use of such pharmaceutical formulations for treating diseases associated with PDE5 inhibitors.

  What happens when lifestyle drugs like Viagra and Cialis lose patent protections?

  April 12, 2017, 11:15 AM 19

  Each year, millions of men rely on pharmaceuticals like Viagra and Cialis for their erectile dysfunction (ED), but they may not be the only ones facing dysfunctionalities. As the patents on these lucrative lifestyle drugs come to an end, price tags and bottom lines are expected to plummet.

  PDE5 Inhibitors

  Viagra made by Pfizer and Cialis by Eli Lilly are phosphodiesterase type 5 (PDE5) inhibitors which break down cyclic guanosine monophosphate (cGMP). In a gross simplification, after sexual stimulation, an erection occurs through the release of nitric oxide (NO) which causes dilation of blood vessels due to an accumulation of (cGMP). Dysfunction occurs when cGMP conflicts with the NO vasodilatory effects. When the PDE5 inhibitor is introduced, the cGMP is broken down. So, less cGMP means more blood flow et voilà, an erection.

  There are differences between these drugs, though. For example, Viagra is made with sildenafil and has a wait time of 30-60 minutes lasting for up to 4 hours. Cialis’ main ingredient is tadalafil and can either be taken daily (meaning it is always active in the body) or 30 minutes to 12 hours before activity to last up to 36 hours. This longer lasting formula is one of the benefits over the “little blue pill” which has proved to be more appealing to most men. Further, sildenafil and tadalafil have different chemical and molecular structures.

  Viagra and Cialis Patent Protection

  The success of these drugs has been guaranteed in large part by securing IP rights across the globe. Viagra was approved by the FDA in the United States in 1998 and Cialis in 2003, but their patent journeys occurred earlier.

  The first patent for Viagra was filed in May 1994and was issued in 2002, but Viagra did not begin as an ED pill. The compound was originally developed and patented as a drug called Revatio to treat high blood pressure (hypertension) and chest pain due to heart disease (angina pectoris), but clinical trials showed that it was more effective at inducing erections than anything else.

  The drug was then renamed and patented as Viagra. Viagra was a pre-GATT application because it was filed before June 8, 1995, so it got the benefit of choosing its expiration date: either 17 years from the issue date of 2002, that is to say October 2019 or 20 years from filing, with rights lapsing in May 2014. Naturally, Pfizer selected the later October 2019 date. Further, through the FDA, the expiration was extended another 6 months to April 2020 due to a special pediatric exclusivity testing Revatio’s effect on pulmonary arterial hypertension.

  With the expiration of Viagra three years away, you would think that the market for generics would be on hold until then. However, an Israeli manufacturer named Teva Pharmaceutical Industries Ltd. will be allowed to sell a generic version of Viagra beginning December 11, 2017. Since several patents outside the US have already expired, an undisclosed deal was arranged after Pfizer sued Teva and Teva was authorized to launch a generic version. The settlement stipulates that the generic manufacturer will have to pay royalties to Pfizer through the April 2020 patent expiration date. Teva’s inventory has already been approved by the FDA for three different strengths of sildenafil citrate and the company has been selling a generic in the European Union since 2013.

  Cialis came to market after an over five-year monopoly of Viagra as the only prescription drug on the market to treat ED. In its first year, Viagra sales revenue exceeded $1 billion, but its profit margins declined with the introduction and FDA approval of Levitra (another ED antidote) in August 2003 and Cialis in November 2003. Cialis was discovered in August 1991 by a company named Icos and was later purchased by Eli Lilly. Patent protection expires at the end of this year, so the company will still be able to register a profit during almost the entirety of 2017 before getting crushed by generics.

  Like Viagra, Cialis is also used to treat pulmonary arterial hypertension and was approved as such in the US in May 2009. Another similarity is that Eli Lilly struck a licensing deal with the French company Sanofi to maximize any profits it possibly can before the patent expires. In 2014, an announcement of this licensing agreement was made where Sanofi will sell an over-the-counter version of Cialis in the U.S., Europe, Canada and Australia when specific patents expire. Lilly will make its money through the licensing fees.

  Another way Pfizer and Eli Lilly have tried to recoup lost sales is by making the drugs over-the-counter medications and selling them directly through their websites. By doing this, the companies goals are to capture sales from those who are too embarrassed by the social stigma of impotence and who do not want to discuss their condition with a doctor.

  Lifestyle vs. Lifesaving Drugs

  Viagra and Cialis are lifestyle drugs. This label means that they treat “lifestyle illnesses” arising from lifestyle choices like smoking, weight gain, and alcoholism or ailments like baldness, dry skin, wrinkles, ED and hot flashes. These medicines may improve a patient’s life, function or appearance and may not be medically necessary or therapeutic. One way to look at them is that they enhance a patient’s life instead of extending it. These are unlike life-saving pharmaceuticals used to cure or manage illness and generally improve health, like cancer or HIV medications. The good news for ED drugs is that they are reasonably secure in their patents under Trade-Related Aspects of Intellectual Property Rights Agreement (TRIPS). It is less likely that countries facing major pandemics like HIV/AIDS, malaria and Zika will be too concerned with needing lower priced drugs for ED, weight loss or crow’s feet, unless the drugs have other, more relevant, implications.

  The lifestyle drug market is extremely lucrative. These medications can be used by all age groups worldwide and increased individual awareness of health and beauty has created a demand for physical fitness and improved performance of all our body parts. People are living longer, have higher disposable income, and the demand only grows more when a drug touts the high quality and safety of their formulations after it passes the stringent requirements for FDA approval. Additionally, a greater number of people are turning to pharmaceuticals to “treat” ordinary ailments, mild symptoms and personal problems, thinking that a pill is the answer to all their problems. Also good for the Pfizers and Eli Lillys of the world is that since the pharmaceuticals are not curing a disease or problem, but rather treating an issue (such as ED, cholesterol or high blood pressure) the patient takes daily doses and usually over many years. This is unlike an antibiotic that is taking for a finite duration and once the taker is cured they no longer need the drugs, effecting that medicines bottom line.

  Further, since lifestyle drugs have a better shot at being successful economically because they can be sold to more people, drug companies are more likely to continue to create and invest in those rather than medicines for, say, malaria, where the patients are fewer and too poor to pay enough to offset the sky-high R&D costs.

  Conclusion

  Lifestyle drugs like Viagra and Cialis have been an extraordinary success for drug companies for many years. It will be difficult to replace the revenue of these blockbuster drugs once they go off patent in the United States, but when that happens consumers can expect generics to race into the marketplace and for prices to fall. The real question, however, is whether U.S. patent law and policy will continue to give pharmaceutical companies the incentives necessary to innovate lifesaving medicines, or whether we will continue to see more and more blockbuster lifestyle drugs moving into the future.

  SHIN & KIM 韩国世宗律师事务所

  On February 3, 2017, the Patent Court of Korea invalidated Korean registered patent no. 0577057, a dosage patent that limits the dosage of Tadalafil, a substance for treating erectile dysfunction contained in Cialis, to 20mg per day and unit dosages to 1mg to 20mg (the “Dosage Patent”).

  After the expiration of the Cialis substance patent on September 4, 2015, about 60 domestic pharmaceutical companies have been making and selling generic versions of Cialis in Korea. If the Dosage Patent were found to be valid, these companies would have been subject to considerable liability for patent infringement. ccordingly, the entire pharmaceutical industry in Korea has been closely following this case.

  This case is all the more significant because it is the first case where the element of inventiveness for dosage patents is considered after the Supreme Court acknowledged in an en banc judgment that dosage regimens for medicines are patentable (2014Hu768 Judgment on the case of confirmation of the scope of a patent right). Representing Chong Kun Dang Pharmaceutical Corp., the leading generic Cialis drug maker in Korea, we researched relevant precedents of the Supreme Court and the courts of the U.K. and Japan and argued that dosages that can be deduced based on prior art through common clinical tests should not be acknowledged as non-obvious, and the significance of such effects should not be acknowledged unless the effects of the proposed dosage can only be achieved by adhering to such dosage regimen.

  ICOS Corporation, the owner of the Cialis patent, argued on the basis of statements of the inventor who conducted the clinical tests and expert witnesses, including a pharmacology professor, that the claimed dosage cannot be deduced by common clinical tests because such low dosages cannot be easily expected from prior arts, as well as asserting that the effects of the Dosage Patent are significant because lower dosages resulted in unexpected pharmacological effects while reducing side effects. However, we presented evidence to the contrary, using documentation made available through the US FDA’s approval process for Cialis and the testimony of expert witnesses. We were able to show that ordinary skilled persons could deduce dosages similar to that of the Dosage Patent by applying their general skills, and the effects of such dosages were not significant when compared with prior art, in terms of treatment or reduction of side effects. Consequently, we argued that the Dosage Patent should be invalidated because it lacked inventiveness.

  The Patent Court accepted our argument and ruled “it is within the scope of ordinary creativity of ordinary skilled persons to optimize dosage conditions, including the amount/cycle of dosage, for enhancing the effects, and reducing side effects, of the disclosed medicine to the extent such optimization does not cause any toxicity or side effect, etc.; provided, however, in extraordinary circumstances, where favorable effects caused by a certain dosage or regimen are significant beyond the scope predicted by ordinary skilled persons, or if ordinary skilled persons cannot predict a certain dosage or regimen that maintains the pharmacological effects of the relevant pharmaceutical invention at the same level, minimizing any toxicity or side effect from the prior art, the inventiveness of such dosage or regimen should not be denied,” presenting clear standards for determining the inventiveness of new dosage patents. Based on these standards, the Patent Court invalidated the Dosage Patent ruling that the Dosage Patent lacked inventiveness given there was no significant difficulty in deducing the claimed dosage through common clinical tests, and that the effects generated within the scope of the dosage claimed by the Dosage Patent were not significant or unique enough to warrant acknowledgement of
  inventiveness.

  This judgment is meaningful because not only does it absolve domestic pharmaceutical companies manufacturing generic versions of Cialis from liability for patent infringement but it also establishes clear standards of judgment for determining the inventiveness of new dosage patents. Original pharmaceutical companies holding a substance patent will now need more than common clinical tests on different dosages to satisfy the necessary element of inventiveness for a dosage patent in Korea.

  When will the patent expire on Cialis?

  What Cialis is, the importance of patent; Cialis patent process and expiration date

  In answering the question, it may be useful to know first what Cialis is and why the issue of patent expiration is important.

  Cialis is one of the brand names for Tadalafil, a drug used to treat erectile dysfunction or persistent difficulty to achieve and maintain an erection of the penis sufficient to have sex. It is similar to other erectile dysfunction drugs, Viagra and Levitra. Tadalafil is also used for treating pulmonary arterial hypertension under the brand name, Adcirca.

  Cialis was discovered in August 1991 by the biotechnology company, Icos Corporation and approved by the U.S. Food and Drug Administration (FDA) in November 2003. It was later purchased by the pharmaceutical company, Eli Lilly and Company, when the patent of the drug was transferred to the company.

  Order effective treatment for erectile dysfunction discreetly

  A patent is a form of intellectual property (non-physical property that is the result of creativity), which gives its owner the legal right to exclude others from making, using, selling, and importing an invention for a limited period of years, in exchange for publishing and enabling public disclosure of the invention at the end of the period of protection.

  Although drug patents last 20 years after the invention of the drug, it can take up to 8 years for a pharmaceutical company to do enough testing for approval from the FDA and investors.

  While other patents have a limited length from the approval date, drug patents follow a different set of rules, which give patent extensions to name-brand drug companies to compensate for delays in the FDA approval process. This allows for a patent extension for up to five years, regardless of the length of time it took for the FDA to approve the drug. It also further caps the protected amount of time to 14 years, depending on the approval delay time frame. This ensures the patent holder can assume profitability before generic drug companies move into the picture and are permitted to manufacture their versions of the identical makeup of the original drug, to encourage price reduction due to competition.

  The patent protection for Cialis was set to expire on April 26, 2020. However, in July 2017, Eli Lilly and Company entered into a settlement agreement with multiple generic companies to resolve pending patent litigation in the court regarding Cialis. As part of the agreement, Eli Lilly’s patent protection of Cialis is expected to have ended at the earliest, on September 27, 2018.

  References

  1. MedicalNewsToday, Cialis: What is it and who can use it?, [website], 2017, https://www.medicalnewstoday.com/articles/232993.php (accessed 12 September 2019).
  2. MedicalNewsToday, What’s to know about erectile dysfunction?, [website], 2017,https://www.medicalnewstoday.com/articles/5702.php (accessed 12 September 2019).
  3. ipwatchdog, What happens when lifestyle drugs like Viagra and Cialis lose patent protections? [website], 2017, https://www.ipwatchdog.com/2017/04/12/lifestyle-drugs-viagra-cialis-lose-patent-protections/id=81619/ (accessed 12 September 2019).
  4. Lilly, Lilly Reaches Settlement Agreement in U.S. Cialis Patent Litigation [website], 2017,https://investor.lilly.com/news-releases/news-release-details/lilly-reaches-settlement-agreement-us-cialis-patent-litigation (accessed 12 September 2019).
  5. upcounsel, How Long Does a Drug Patent Last? [website], 2019,https://www.upcounsel.com/how-long-does-a-drug-patent-last (accessed 12 September 2019).

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