Generic drug approval in the United States - ANDA regulations

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Drug development in the US and FDA approval Procedures: Protection of Pharmaceutical Intellectual Property Rights.

Drug development in the US and FDA approval Procedures.Protection of Pharmaceutical Intellectual Property Rights

US rules for a Japanese audience (reprint of a talk originally given in 2008, partially updated for 2016)Stephen E. Zweig, Ph.D., JD.; Patent AttorneyPatentassociate.com

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2008 Stephen Zweig

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Speakers backgroundPh.D. Biophysics (UCSD), JD Taft Law SchoolFormer Pharmacology Asst. Prof. (Baylor)Director R&D, Johnson & JohnsonFounder, Avocet Medical, Inc. (VC backed startup)10 years CEO/CTO/Chairman experience Business, FDA, Clinical Trial, & R&D managementPresently patent attorney at patentassociate.com

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Overview of talk:1: Cultural and legal differences between the US and Japan2: Review of US Food and Drug Administration (FDA)3: Review of US patent office (USPTO) and patent rulesBreak3

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Overview of talk:4: Hatch-Waxman act: connecting the FDA and the USPTO (continued)5: Drug patent extension and regulatory exclusivity rules6: Patent issues during drug R&D, and the Bayh-Dole act7: Recent changes in US patent law: impact of KSR v TeleflexBreak

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Overview of talk:

8: Orange Book examples of FDA & USPTO interconnections (topical drugs)

Questions

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1: US and Japan differencesUS still has some Wild West influences: Japan has a higher preference for mediation and conciliation. US is more likely to litigate.US tends to view patent claims more broadly than Japan6

Tombstone, Arizona, 1882

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1: US and Japan differencesDifferences in legal systems: Japan has a mixed common/civil law system Judges decisions mostly impact specific cases US & British common law system Judges decisions on specific cases have greater impact on establishing new law and impacting other casesUS lawyers always citing specific court cases as a result these court cases can act to redefine or reinterpret US regulations & laws

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Where common law is used8

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2: Review of the US FDA

History:In 1902, Biologics Control Act. started regulating vaccinesIn 1906, FDA started regulating drugs In 2008, the two parts are still somewhat separate: the biologics division is called CBER and handles biotech drugs, and the drug division is called CDER, and handles drugs and antibiotics. They dont always use the same rules!

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FDA organization10

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FDA Drug approval stagesDrug approval stages: Investigational new drug (IND)Phase I (small numbers of humans for safety)Phase II (small numbers of humans for efficacy)Phase III (large numbers of humans for safety/efficacy)Phase IV (post marketing studies)

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New drugs & generic drugsNew (first time) drugs filed by New Drug applications (NDA) massive effortGeneric (copy) drugs filed by Abbreviated New Drug Applications (ANDA). ANDA are easier to file because they can make use of previous NDA clinical studies and data.12

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Hatch-Waxman actHistory1980s crisis: FDA drug approval time became so long that drugs were almost off-patent by the time of FDA approval. At the same time, generic drug companies could not start studies before patent expiration due to patent infringement issues. Both sides suffered.

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Hatch-Waxman act1984 Hatch-Waxman act: Extended exclusive lifetime (patent, FDA exclusivity) for new drugs in exchange for allowing generic drug companies to start FDA approval studies before patent expiration.

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Hatch-Waxman rules:Patent extension starts on day of initial filing, ends on FDA approval, get 1 day credit for every day of FDA delay, and day credit for every day of applicant delay, up to a maximum of 5 years, for the claims directed to the approved drug only. FDA communicates dates to patent office, which publishes patent term extension dates.

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Effect of Hatch-Waxman16

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The orange bookThe Orange book is the nickname for the FDAs Approved Drug Products List with Therapeutic Equivalence EvaluationsFirst published in 1979In 1984, FDA started adding patents to the Orange book to keep track of which drugs are covered by patentsWe will come back to this later in more detail

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3: Review of the USPTOPatents are part of US constitution. First patent granted soon after federal government formed in 1790. Initially run by Thomas Jefferson, who stored patents in his old shoeboxes!Prior to 1995, US patent term was 17 years after issue

18 After 1995, US conformed to WIPO rules of 20 years after filing, but a US inventor can file a provisional patent to get an extra year (21 years total).

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US patent rulesUS has a modified first to file systemUS rules allow for continuations, new patents based on old patents. Japanese patent applications treated favorably using PCT system

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US patent requirementsUtility: - 35 USC 101 (compounds and targets must have a plausible function)Novel: - 35 USC 102 (defeated by single reference)Non-obvious: 35 USC 103 (defeated by a combination of references) the 2007 KSR decision now makes it easier to challenge on the basis of obviousness20

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US patent requirementsContain detail: - 35 USC 112 described with enough detail (how to manufacture)Be invented by the applicant for the client (must get proper assignment)Must be filed within 1 year of publication anywhere or first US sale.

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Public use bar:Patent aspects of clinical trials in the US: the public use bar: Although filing before public use is best, patents can be filed within one year of first public use or sale in the US.

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Patents relevant to drugs1: Compound patents (broadest drug, salts, esters, hydrates)2: Medical use patents (treating specific diseases)3: Formulation patents (stabilizers, preservatives4: Other (manufacturing, device, etc.)

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Types of drug patentsUS drug patents can be on the form of the active compound: sterioisomers, polymorphs, salt forms, in-vivo conversion, particle size, formulations, manufacturing process, combination of therapies, methods of treatment, drug delivery systems, and other areas.

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Other US patent aspectsUS Patent office overburdened and patents take years to issuePatents may have continuations and continuations in part Patents may be reissued sometimes may have broader claims No opposition, but patents can be reexamined only publications usedMain way to challenge patents is in the courts

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TrademarksThe US patent office also handles trademarks -- drug color, pill size and shape, name can also be protected26

http://tess2.uspto.gov/bin/gate.exe?f=searchss&state=b9nsj7.1.1

25 trademarks with the words skin cream

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Break oneQuestion:

Where did Thomas Jefferson, first commissioner of the US patent office, and later the 3rd US president, store the first US patents?

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AnswerLegend has it that he stored them in his shoeboxes under his bed.28

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4: Hatch-Waxman act: connecting the FDA and the USPTOThe Orange book: FDA list of approved drugs, approval dates, indication, regulatory exclusivity, and the patents that cover each drug.The patent list includes active drug, formulation, inactive ingredients or excipients, approved medical indications.The patent list does not cover manufacturing method patents, metabolites of the active drug, manufacturing intermediates, packaging and container patents29

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Generic drug approvalGeneric drugs can get approval if they show that their drug is bioequivalent to original drug by filing an ANDA that can reference the original drug NDA

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Generic drugs and patentsWhen a generic drug company files an ANDA application, it must examine the status of the drug patents from the Orange Book, and certify that either: 1: There is no patent information listed2: There is a listed patent but it is expired3: That the listed expired will expire on a stated date (usually soon)4: That the listed patent is invalid or will not be infringed.

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Examples:1: There is no patent information listed2: There is a listed patent but it is expired

If a generic drug manufacturer certifies 1 & 2, then the FDA starts processing the generic ANDA right away

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Examples:3: That the listed patent has expired or will expire on a stated date (usually soon)

If a generic drug manufacturer certifies 3, then the FDA starts processing the ANDA, and gives approval when the patent expires

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The start of a patent fight!4: That the listed patent is invalid or it will not be infringed.ANDA filer notifies patent holder within 20 daysPatent holder must sue for infringement within 45 days If the patent holder sues, FDA must withhold approval for 30 months (one time only)If the patent holder does not sue, FDA may approve ANDA at any timeIf a court rules that the patent is not infringed or invalid, FDA may proceed after decision.34

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Be carefulA US company may also wait, and then sue after the generic drug is approved.

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5: Drug patent extension and regulatory exclusivity rulesA: A new drug can get up to 5 years patent extension to make up for FDA delaysB: The first generic ANDA filer gets 180 days exclusivity (per product)C: New chemical entities get a 5 year ban on use of their NDA data for generic ANDA applications.

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5: Drug patent extension and regulatory exclusivity rulesD: Orphan drugs (use less than 200,000 US patients) get a 7 year hold on other NDA and ANDA applicationsE: New therapeutic use or new formulation gets a 3 year hold on ANDA FDA approvalF: Pediatric exclusivity gets a 6 month additional hold on FDA approval of any ANDA applications

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Research using drugs under patentResearch using drugs still under patent: US 35 USC 271(e)(1)

1) It shall not be an act of infringement to make, use, offer to sell, or sell within the United States or import into the United States a patented invention solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products.

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Strategy:Generic companies frequently file for an early ANDA long before patent expiration in order to get the 180 day exclusivity. They then challenge the patent as either being invalid or not being infringed, and hope that the US courts agree with them.

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6: Patent issues during drug R&D, and the Bayh-Dole act

A: US has a modified first to file system.B: In the US, the inventions are owned by the inventors first, not the companyC: Must be careful with ownership issues: Need to understand and clarify 1: When does invention occur?2: Who are the inventors?Academic (can accidentally ruin patents by early publication)Within a single companyJoint inventorship

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Who owns the US patent?Who actually owns the patent?Research agreement if no agreement is joint inventorshipMuch US drug & biotech R&D is government funded for government funding, the Bayh-Dole act controls the government ownership issues.

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The Bayh-Dole actBefore Bayh-Dole, the US government owned all US government-funded research. But nobody did anything with the inventions!After Bayh-Dole, university/business owns government funded research, if the institution complies with law 35 USC 200 212. These rules are that the institution must:42

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The Bayh-Dole act1: Promptly disclose invention to the funding agency2: Ask for title to the invention within two years3: File a patent application before it is too late4: Give the funding agency license to the invention5: Periodically (annually) file reports to the agency

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The Bayh-Dole act6: State that the government has rights on the patent application7: Preferably license to small US firms8: If there is exclusive license, licensee must agree to manufacture in the US!

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35 USC 204 Preference for US industry:

no assignee of any such small business firm or nonprofit organization shall grant to any person the exclusive right to use or sell any subject invention in the United States unless such person agrees that any products embodying the subject invention or produced through the use of the subject invention will be manufactured substantially in the United States. However, in individual cases, the requirement for such an agreement may be waived by the Federal agency under whose funding agreement the invention was made upon a showing by the small business firm, nonprofit organization, or assignee that reasonable but unsuccessful efforts have been made to grant licenses on similar terms to potential licensees that would be likely to manufacture substantially in the United States

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The Bayh-Dole actE: Failure to comply with Bayh-Dole: a competitor may use the failure to comply with Bayh-Dole as an excuse to attack the drugs patents

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Obviousness in US patent law: impact of KSR v TeleflexPatent crisis in US computer and electronics products covered by so many patents that it is difficult to make new products. These companies want fewer and weaker patents. However drug and biotech companies depend on small number of strong patents, and do not want to make patents weaker. US Supreme Court decided that it was too easy to get obvious patents, and decided to make obvious patents both harder to get and easier to challenge.

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KSR v Teleflex48

The patent claimed a electronic throttle control mounted to a pedal support

Prior art was very close, such as a pedal with pivot cables going to throttle controls.

Other prior art included an electronic potentiometer throttle control mounted on the pedal support bracket

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KSR v TeleflexKSR v Teleflex (2007): Old US rules were that to be obvious, the examiner had to find proof of a prior art, teaching, suggestion or motivation (TSM) to produce the inventionThere was none here, but the patent still looked too obvious anyway Supreme Court made it easier to invalidate patents by stating that this old TSM rule was not sufficient. Even without prior art TSM, some patents may still be obvious.

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KSR v TeleflexSupreme Court Justice Steven Breyer joked that if he had to move a sensor on his garage door because raccoons were gnawing on it, should he be able to patent this?50

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KSR v TeleflexThe Supreme Court ruled: And as progress beginning from higher levels of achievement is expected in the normal course, the results of ordinary innovation are not the subject of exclusive rights under patent laws. 127 S. Ct. at 1745.The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results. 127 S. Ct. at 1739.A person of ordinary skill is also a person of ordinary creativity, not an automaton. 127 S. Ct. at 1742.

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KSR v TeleflexOne of the ways in which a patents subject matter can be provedobvious is by noting that there existed at the time of invention a knownproblem for which there was an obvious solution encompassed by thepatents claims. 127 S. Ct. at 1742.Common sense teaches, however, that familiar items may haveobvious uses beyond their primary purposes, and in many cases aperson of ordinary skill will be able to fit the teachings of multiplepatents together like pieces of a puzzle. Id.

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KSR v TeleflexWhen there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp.

Net effect: makes it easier to invalidate patent applications & patents as being obvious:

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KSR v TeleflexImpact of KSR still being felt. As a guideline, a patent is likely to be non-obvious if prior art teaches away from the claimed invention or if the patent has advantageous properties unexpected from the prior art.

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KSR v TeleflexD: Some examples of drug patents that now may be obvious:[S]tructural similarity between claimed and prior art subject matter, proved by combining references or otherwise, where the prior art gives reason or motivation to make the claimed compositions.

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KSR v TeleflexD: Some examples of drug patents that now may be obvious:

Structural similarity, alone, may be sufficient to give rise to an expectation that compounds similar in structure will have similar properties

When chemical compounds have very close structural similarities and similar utilities

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KSR v Teleflex: non-obvious patentTakeda v. Alapharm (Actos) 492 F.3d 1350 (Fed. Cir. 2007).

Patented drug Prior art

The court ruled: Not obvious because prior art had toxic side effects that taught away from its use, and no reasonable expectation that the modification would reduce toxicity.

In order for it to be obvious, there must be some reason that would have led a chemist to modify a known compound in a particular manner, and a suggestion to have made this specific modification.

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KSR v Teleflex: Aventis v. Lupin (Altace) An ACE inhibitor Ramapril is the SSSSS configuration of a compound with 32 possible stereoisomers, prior art was a mixture of SSSSS and SSSSR. A similar ACE inhibitor enalapril is 700x more powerful in the SSS form than the SSR form. Ruled obviousThe court ruled: one skilled in the art would have expected ramapril to be more potent based on the example of enalapril and there was no evidence that separating ramapril was outside the skill of the art. If it is known or believed that some desirable property of a mixture derives from a particular one of its components, the purified compound is obvious over the mixture even without an explicit teaching that the ingredient should be concentrated . Additionally, there were no unexpected results

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KSR v Teleflex: Pfizer v. Apotex (Norvasc)

Patent claimed the besylate salt form of amlodipine as superior to the prior art maleate salt form of amlodipine (better stability).

Prior art disclosed that besylate salt used as 1 of the 53 salts used in FDA approved drugs, used in about 1 out of 400 drugs. Also used in other prior art patents.

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KSR v Teleflex: Pfizer v. Apotex (Norvasc)

The court ruled: Sufficient motivation existed to combine prior art to make amlodipine besylate; one skilled in the art would have narrowed the genus of 53 salts to a few, including benzene sulphonate.there was a reasonable expectation of success because the prior art patent contained a strong suggestion that any and all pharmaceutically acceptable anions would work for amlodipine..there was a reasonable expectation of success, which could be verified by routine testing.

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Break twoWhat do raccoons have to do with US patent law?61

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AnswerUS Supreme Court Justice Breyer, during review of KSR v. Teleflex, compared the invention to a problem he had with raccoons chewing on the sensor part of his garage door opener. If he moved the sensor up out of the reach of the raccoons, would the (pre KSR v. Teleflex) patent law let him get a patent on that? 62

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8: Orange Book examples of FDA & USPTO interconnections (topical drugs)

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Examples:

A generic company wants to produce a new topical generic drug. What might be a good possibility?

Search for Topical in 2008 Orange book, get 427 hits

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An example of a topical drug listing

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Another topical drug listing

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Generic drugs and patentsWhen a generic drug company files an ANDA application, it must examine the status of the patents from the Orange Book, and certify that either: 1: There is no patent information listed2: There is a listed patent but it is expired3: That the listed expired will expire on a stated date (usually soon)4: That the listed patent is invalid or will not be infringed.

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The start of a FDA patent fight!4: That the listed patent is invalid or will not be infringed.ANDA filer notifies patent holder within 20 daysPatent holder must sue for infringement within 45 days If the patent holder sues, FDA must withhold approval for 30 months (one time only)If the patent holder does not sue, FDA may approve ANDA at any timeIf a court rules that the patent is not infringed or invalid, FDA may proceed after decision.67

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US patent checkHave any other generic drug companies decided to challenge the validity of any drug patents for topical drugs? Can check this by going on the web at: http://www.fda.gov/CDER/ogd/ppiv.htm

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Paragraph IV issuesParagraph IV Patent Certifications

The PDF contains a list of drug products for which an Abbreviated New Drug Application (ANDA) has been received by the Office of Generic Drugs (OGD) containing a "Paragraph IV" patent certification. This list includes the name of the drug product, dosage form, strength (subject of Paragraph IV certification), reference listed drug (RLD),and the date on which the first substantially complete generic drug application was submitted to the Agency (on a prospective basis beginning 3/2/2004). The Agency will not disclose the identity of the applicant.69

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Topical drugs in a FDA patent fightDrug NameDosage FormStrengthRLDDate of SubmissionCalcipotrieneTopical Solution0.005%Dovonex5/19/2006Clobetasol PropionateTopical Foam0.05%Olux6/27/2005Clobetasol PropionateLotion0.05%Clobex3/27/2006ImiquimodCream5%Aldara10/17/2006Mometasone FuroateTopical Solution (Cream)0.1%EloconMometasone FuroateTopical Solution (Lotion)0.1%Elocon6/10/2004Silver SulfadiazineCream1%SilvadeneTretinoinCream0.025%, 0.05% and 0.1%Retin-A

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Mometasone furoate (Mometasone)a moderately potent glucocorticoid steroid used in the treatment of inflammatory skin disorders (such as eczema and psoriasis)

What patents made the generic drug company decide to file a category IV (4) patent challenge with the FDA?

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Check patent status in Orange book72

Go here to search by ingredienthttp://www.accessdata.fda.gov/scripts/cder/ob/

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http://www.fda.gov/cder/ob/docs/queryai.htm

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Enter drug name

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Mometasone Furoate cream74

http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=019625&TABLE1=OB_RxLook here for patent information

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No FDA listed patents 75

Mometasone Furoate creamThe FDA will not delay an ANDA filing for this drug

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Calcipotriene cream76

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Calcipotriene cream77

Look here for patent information

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Calcipotriene cream does have patents78

Recently expired patentDoesnt expire for a long time!

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What is going on here?Why did the generic drug company file a category IV (4) ANDA application for the Calcipotriene topical cream if the drug was covered by a patent(s) 5,763,426 and RE39706 that do not expire until June 9, 2015? 79

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Now we go to the USPTO web site80

http://patft.uspto.gov/netahtml/PTO/srchnum.htmEnter the patent number

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Download patent 5,763,426 81

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Look at 5,763,426 claims:1. Calcipotriol monohydrate characterized by its storage stability at 40.degree. C. after 12 months, its ready wettability and wet ball milling characteristics.

2. Pharmaceutical composition containing the compound of claim 1.

3. Pharmaceutical composition according to claim 2 which is a cream.

4. Pharmaceutical composition according to claim 2 which is a gel.

5. Pharmaceutical composition according to any one of claim 4, with a content of the active component of 1-100 .mu.g/g of the composition.

6. The method of preparing calcipotriol monohydrate which comprises dissolving calcipotriol in organic solvent and then adding water to the resulting solution to precipitate the hydrate, said hydrate being characterized by its storage stability at 40.degree. C., its ready wettability and wet ball milling characteristics.

7. In the preparation of a gel formulation which involves wet ball milling a calcipotriol component and adding the wet milled calcipotriol component to a gel base, the improvement which comprises wet milling calcipotriol hydrate as said component and using this wet milled hydrate for addition to said gel base, said hydrate being characterized by its storage stability at 40.degree. C. after 12 months, its ready wettability and wet ball milling characteristics.

82Claim 3 covers the cream

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5,763,426 covers the creamSince 5,763,426 covers the topical cream form of Calcipotriene, and the patent doesnt expire until 2015, why did the generic drug company file the category (IV) (4) ANDA?83

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The ANDA was for Topical SolutionDrug NameDosage FormStrengthRLDDate of SubmissionCalcipotrieneTopical Solution0.005%Dovonex5/19/2006Clobetasol PropionateTopical Foam0.05%Olux6/27/2005Clobetasol PropionateLotion0.05%Clobex3/27/2006ImiquimodCream5%Aldara10/17/2006Mometasone FuroateTopical Solution (Cream)0.1%EloconMometasone FuroateTopical Solution (Lotion)0.1%Elocon6/10/2004Silver SulfadiazineCream1%SilvadeneTretinoinCream0.025%, 0.05% and 0.1%Retin-A

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5,763,426 covers the cream1. Calcipotriol monohydrate characterized by its storage stability at 40.degree. C. after 12 months, its ready wettability and wet ball milling characteristics.

2. Pharmaceutical composition containing the compound of claim 1.

3. Pharmaceutical composition according to claim 2 which is a cream.

85Since the cream is different from the topical solution,The generic drug company probably thought that they were not infringing on patent 5,763,426

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Is the generic drug company OK?86

Look at RE39706US patent rules allow an inventor to file for a broadening reissue as much as two years after a patent has issued!

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RE39706 is a reissue of 5,763,42687

Go back to the USPTO web site and investigate RE39706.

RE39706 issued recently on June 26, 2007, after the generic drug company filed with the FDA

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Claims for RE39706

1. Calcipotriol monohydrate characterized by its storage 40 stability at 40 C. after 12 months, its ready wettability and its suitability for wet ball milling [characteristics].2. Pharmaceutical composition containing the [compound] calcipotriol monohydrate of claim 1.3. Pharmaceutical composition according to claim 2 which is a cream.4. Pharmaceutical composition according to claim 2which is a gel.5. Pharmaceutical composition comprising calcipotriol monohydrate according to any one of [claim 4] claims 2-4 and a pharmaceutically acceptable vehicle, with a contentof the [active component of] calcipotriol monohydrate being 1-100 ug/g of the composition.12. Pharmaceutical composition according to claim 2 which is an ointment.13. Pharmaceutical composition according to claim 2 which is a lotion.14. Pharmaceutical composition according to claim 2 which is a solution.

88The newer claims are broader and cover a topical solution!

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What might have happenedWhen the generic ANDA was filed on 5/19/2006, the 5,763,246 patent only covered creams. On June 26, 2007 however, the reissue of RE39706 of this patent issued, which now also covers topical solutions. Is the generic companys ANDA in trouble? We will have to wait and see89

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References:

90IP conferences:(2007 Conference)

Courses:Pharmaceutical and BiotechPatent Law, by Kaye Scholer, LLP

http://www.pli.edu/product/book_detail.asp?ptid=501&stid=59&id=EN00000000040242

http://www.americanconference.com/Pharmaceuticals_Biotech_Life_Sciences/PBPatentBC.htm

Books:The generic challenge, By Martin. A. Voethttp://www.amazon.com/Generic-Challenge-Understanding-Pharmaceutical-Life-Cycle/dp/1581124309

http://www.aipla.org/

Societies:American Intellectual Property Law Association

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Disclaimer:

This talk was originally prepared in 2008. Although many of the issues discussed here have not changed significantly since 2008, certain sections may be dated. Thus you should check to for changed regulations or laws.

This talk is not intended to give legal advice.91

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Contact information:Stephen E. Zweig, Ph.D., JDPatent AttorneyPatentassociate.com15466 Los Gatos Blvd. 109-355Los Gatos, CA 95030Phone: (408) 348-1495Email: szweig@patentassociate.com

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