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Wed, Dec. 2, at 11:00 AM ETSponsored by: Enterprise Holdings Inc.
Thurs, Dec 17 at 11am ET / 8am PTSponsored By: Global Guardian
Mon, Nov 23 at 12pm ET / 9am PTSponsored in Part By: DEEM, IHG, Southwest Airlines & TripActions
Virtual Event - December 1, 2020
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Filter in or out as many as 200 cities, as well as hotel and car rental class and meals of the day and watch as the per-diem calculator automatically adjusts per diems to your program. Drill down into cost breakdowns and export the results.
Multi story, ultra modern Hotel, popular guest amenities for the business or leisure traveler; located across the Congress Centre.
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TaraChambler. Comforter Ideas. November 01st , 2020.
There are many great Comforter Ideas available today. You can buy the same comforter that you have had for years, but now you can also get your comforter from online stores. Here are some great Comforter Ideas for your home to help you choose the perfect one that will look great in your room and help you feel comfortable in your bed and room.
It seems like people are always looking for new and better Comforter Ideas. For some, it's because they are tired of the same old colors, or it's just because they have a hard time deciding between the many different types available on the market today.
There are a lot of different ideas that you can use to decorate your bed and a few great ideas for comforters. Here are some great ideas for you to choose from.
To find the best Comforters Ideas, you need to consider several factors which include: how much space you have in your bedroom, how comfortable are you with wool, how much natural wood you would like to use, and where do you intend to put the comforters. You should also take into account the room temperature and the type of room you have and the weather in your area.
The most basic type of comforter is the one that you use as a bedtime blanket, with a box spring, and without any other accessories. The type made from thick wool and has a soft velvety feel to it is also a good option. You can find these comforters in most stores, at most online stores, and even from specialty retailers.
If you are looking for a new comforter, then you are sure to be overwhelmed by all the choices available. From basic bedding comforters to luxurious quilts, you will certainly find something that will fit your budget and tastes. So, whether you're looking for a basic bedding comforter or a sophisticated quilt, this article will help you sort through all of the options available.
Are you searching for the right kind of Comforters Ideas? For people who have a lot of space available, there are plenty of comforters to choose from, and you don't even need to do much to them to make them look more attractive. There are a variety of designs available that can easily blend in with your existing decor without making a big deal out of your budget.
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State Farm Insurance Agent View Licenses
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Auto insurance in Fort Worth Home & Renters insurance Member of Hispanic Chamber of Commerce Long time resident of Fort Worth
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Bicycle commuting can be beneficial to your health as well as the environment. If you bike to work, learn how to stay safe on your two-wheel commute. Read more
There are a few things to consider when buying an RV. RVs come in many shapes and sizes, so how do you ever decide? Start by answering the following three questions. Read more
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Investors should carefully consider investment objectives, risks, charges and expenses. This and other important information is contained in the fund prospectuses and summary prospectuses which can be obtained by visiting the prospectus page on statefarm.com. Read it carefully. AP2020/03/0336
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State Farm Bank ®, F.S.B., Bloomington, Illinois, is a Member FDIC and Equal Housing Lender. NMLS ID 139716. The other products offered by affiliate companies of State Farm Bank are not FDIC insured, not a State Farm Bank obligation or guaranteed by State Farm Bank, and may be subject to investment risk, including possible loss of principal invested. The Bank encourages any interested individual(s) to submit an application for any product(s) offered by the Bank. We also encourage you to obtain information regarding the Bank's underwriting standards for each type of credit or service offered by visiting statefarm.com or by contacting the Bank at 877-SF4-BANK (877-734-2265). Callers who are hearing or speech impaired should dial 711 or use a preferred Telecommunications Relay Service. To apply for a Bank product, you may also see your participating State Farm agent.
Life Insurance and annuities are issued by State Farm Life Insurance Company. (Not Licensed in MA, NY, and WI) State Farm Life and Accident Assurance Company (Licensed in New York and Wisconsin) Home Office, Bloomington, Illinois.
State Farm VP Management Corp. is a separate entity from those State Farm entities which provide banking and insurance products. Investing involves risk, including potential for loss.
Neither State Farm nor its agents provide tax or legal advice. Please consult a tax or legal advisor for advice regarding your personal circumstances.


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Bulgarian MiG upgrade plan scraps idea of acquiring F-16s
NO F-16s: The Bulgarian government approved a plan Sept. 20 to upgrade the air force's fleet of MiG-29 fighters to meet NATO standards, effectively scrapping a previous plan to acquire F-16s. Bulgaria, a NATO partner country, still intends to meet NATO interoperability requirements, but the defense...
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Selena Gomez & The Scene [2 nove pesme]Autor popmusic | 18 Jun, 2011
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Spectrum fees, AOL, other charges may increase
Except the economy improves, telecoms operators may see an increase in some of the fees they pay to the Federal Government. Specifically, charges including Spectrum fees, Annual Operating levy (AoL), Numbering fees, and a host of others may be reviewed upward.
Yadudu… and the new direction at FAAN
I was director of airport operations for two-and a-half years before I became the managing director. So, most of the issues that are on ground, I'm not unfamiliar with them.
NCC kicks as some operators refuse to pay AOL
Nigerian Communications Commission (NCC) has decried the non-compliance of telecommunications operators to the payment of the Annual Operating Levy (AOL). Funlola Akiode, Director, Licensing and Authorisation, NCC, said during the Annual Stakeholders' Consultative Forum on Selected Licence Categories in Lagos, that such act was a breach of operators' obligation. Represented by Chukwuma Azikiwe, Head, Post…
NCC, FIRS get joint revenue quality assurance committee for telecoms
In order to improve the level of efficiency in tax management and revenue generation through deployment of technology, the Nigerian Communications Commission (NCC) and the Federal Inland Revenue Services...
AOL plus Yahoo to equal new Oath
AOL and Yahoo will be combined into a unit called Oath after telecom titan Verizon buys the pioneering internet firm, according to a tweet Monday by the AOL chief.


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This report gives overview of the three subsequent courses of the 'Investigative Interviewing' training held in the period of June - July 2007 by the Training Division, Police Development Department, of the OSCE Spillover Monitor Mission to Skopje. Analysis of the feedback forms from the participants and evaluation of the overall course are included.
This brochure intends to make a distinction between freedom of expression and hate speech, both from a terminology and a legal point of view, as well as to differentiate them from other related concepts, such as defamation and insult.
This report, produced by the SPMU, contains an executive summary , summaries of each sessions, an agenda and a list of participants of the workshop that took place on 20-21 October 2010 in Vilnius, Lithuania.
The regional threat assessment was made as part of a regional project aimed at enhancing capacities for strategic analysis and strategic assessments in the Serbian, Montenegrin and Macedonian Ministries of the Interior and was implemented by the OSCE Mission to Serbia. International partners included DCAF and Europol.
This report, produced by the SPMU, contains a summary of the sessions, as well as the final agenda and list of participants of the Regional workshop that took place on 14-15 July 2009 in Almaty, Kazakhstan


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To the amazement of all those who believed in the starlet's condition only of superficial and brilliant things, I discovered a rather dark past in the life of Paris. Maybe he was in his 40s and felt the need to move forward with something more consistent than the usual arrests for cocaine possession or driving under the influence of alcohol. Maybe it's fashionable to fall victim now, when America eats any #MeToo news on bread, and then an emotional story, about surviving repeated physical and emotional aggression, can't hurt.
For whatever reason, Hilton put on a beautiful make-up and arranged herself in front of the camera and talked about her traumatic adolescence and the five ex-boyfriends who beat her. "I've had a lot of abusive relationships in my life," she told People. "I was strangled, I was brutally beaten and grabbed. I endured far too much of what no one should bear, "says the woman who has been engaged three times (with Jason Shaw, Paris Latsis and Chris Zylka), but has not had a wedding or marriage so far.
Read the rest of Paris Hilton's story in OK! Magazine.


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Download PDF | ePub | DOC | audiobook | ebooks
Analog Integrated Circuits (Solid State Science and Engineering Series)
[PDF.ex59] Analog Integrated Circuits (Solid State Science and Engineering Series)
Analog Integrated Circuits (Solid Edwin W. Greeneich epub
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Analog Integrated Circuits (Solid Edwin W. Greeneich pdf file
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| #4211505 in Books | Edwin W Greeneich | 1997-02-28 | Original language:English | PDF # 1 | 9.21 x.81 x6.14l,1.53 | File type: PDF | 341 pages | Analog Integrated Circuits
||0 of 0 people found the following review helpful.| Better than Serda-Smith Book.|By Juan Gustavo Sanchez|I like to design Discrete Op Amps to use them as Headphones Amplifiers, and in this book I found all the theory and formula that I need.|0 of 0 people found the following review helpful.| Five Stars|By Donald A. Patterson|Veryclearboom with lots of examples.|1 of 1 people f|From the Back Cover|This up-to-date text offers a clear and comprehensive presentation on the design and analysis of modern analog circuits using integrated bipolar and field-effect transistor technologies. Basic "building blocks" common to most analog integrate
Analog Integrated Circuits deals with the design and analysis of modem analog circuits using integrated bipolar and field-effect transistor technologies. This book is suitable as a text for a one-semester course for senior level or first-year graduate students as well as a reference work for practicing engin eers. Advanced students will also find the text useful in that some of the material presented here is not covered in many first courses on analog circuits. Incl...
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Professor Layton Review
Posted: A year ago, last updated 7 months ago.
Author: Andy Robertson.
The following adventures are available:
- Professor Layton and the Curious Village (2008) on Nintendo DS.
- Professor Layton and the Diabolical Box/Pandora's Box (2009) on Nintendo DS.
- Professor Layton and the Unwound Future/Lost Future (2010) on Nintendo DS.
- Professor Layton and the Last Specter/Spectre's Call (2011) on Nintendo DS. It includes an RPG called Professor Layton's London Life.
- Professor Layton and the Miracle Mask (2012) on Nintendo 3DS. The game features daily puzzles
- Professor Layton and the Azran Legacy (2013) on Nintendo 3DS.
- Layton's Mystery Journey: Katrielle and the Millionaires' Conspiracy (2017)on Nintendo 3DS
- Layton Brothers: Mystery Room (2013) on iOS, Android.
- Professor Layton vs. Phoenix Wright: Ace Attorney (2012) on Nintendo 3DS a crossover between the Professor Layton and Ace Attorney series.
Rating: PEGI 7+, ESRB EVERYONE 10+
Release Date: 07/11/2008
Platforms: Android, Nintendo 2DS|3DS, Nintendo DS, Nintendo Switch and iOS
Genres: Adventure, Narrative, Puzzle and Turn-Based
View our choice of games like Professor Layton. This game is good if you want to:
Age Ratings
This game has been rated ESRB EVERYONE 10+.
Layton's Mystery Journey received a PEGI 7 because it features contains violence against humans that is not shown but is implied. The game contains comprehensive anime cutscenes. Some feature scenes containing implied violence towards human-like characters.
System Settings
Android has accessibility settings including ways to navigate and interact, although not all games support this. Nintendo Switch has some built-in features, including a lockable zoom, that can be used on all games. iOS has a very extensive suite of accessibility settings including ways to navigate with voice and comprehensive screen reading, though most of the features don't work with games... read more about system accessibility settings.
Games Like Professor Layton
The following games are like Professor Layton. They address a similar topic or offer a similar way to play. They are good options to play next and also good alternatives to Professor Layton for younger age ratings.
Thank you for using our resource, supported by AskAboutGames, ParentZone and PlayAbility Initiative. We are editorially independent, written by parents for parents, but welcome sponsorship, partnership and suggestions. Email our editor for details on these opportunities.
The information on this database is designed to support and complement the in-depth discussion and advice about video game "addiction", violence, spending and online safety in the Taming Gaming book. If you have any concerns or questions in these areas, email our editor who is quick to respond or can arrange for a one-to-one conversation.


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Flint, Michigan – The Charles Stewart Mott Foundation granted $1,051,000 to Flint Community Schools (FCS) to purchase additional technology the district needs to continue delivering educational content to students in a remote learning environment.
The funds will be used to purchase 600 iPads, 1,200 Chromebooks and 1,400 mobile Wi-Fi hot spots to help students and families stay connected with educational, afterschool, community education, and health and wellness resources.
"Every student deserves to stay connected to the resources they need to be successful," said Ridgway White, president and CEO of the Mott Foundation. "We hope these funds will help students and families in our community have access to technology when they need it most."
The latest funding is an increase to an earlier grant of $163,000 that Mott awarded to FCS in April to purchase 800 mobile Wi-Fi hot spots and 1,500 Mobile Guard applications. This grantmaking supports Mott's goal of strengthening the capacity of FCS to help students succeed both inside and outside the classroom.
The additional funding will ensure all FCS students have the technology they need for learning at home. The hot spots will support students who do not have high speed internet at home capable of supporting virtual learning, as well as students who are cared for by multiple family members or neighbors and need to have internet access wherever they're learning. When students are able to return to school, they also will have access to some additional devices available in school buildings.
The grant also will be used to upgrade decade-old wireless access points in the district's schools and its administration building. This will allow school staff, as well as staff operating YouthQuest and community education programs, to have more reliable internet access within the schools.
"Through the generous support of the Mott Foundation, we have been able to secure critical access to technology, which makes virtual learning possible for all Flint Community Schools students," said Superintendent Anita Steward. "This additional funding will allow us to prepare for in-person technology needs, expand accessibility in the school buildings and rapidly replace devices throughout the year. It's just another way our essential community partners are helping us stay Flint focused and ensure families can overcome any obstacles they may encounter."
For more information, parents and guardians can contact their child's school principal.


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Download End-of-Life Communication in the ICU: A Global Perspective by David W. Crippen PDF
By David W. Crippen
Advances in expertise have ended in a world community of physicians within which info, info, and practices might be brazenly shared to aid make sure top of the range care. End-of-Life conversation within the ICU is a manifestation of this trust multiplicity of views may also help within the decision-making technique. The ebook, with contributions from a various staff of leaders within the foreign ICU group, examines how diverse cultures view demise and explores how healthcare companies worldwide converse to sufferers and family such delicate concerns as withholding or taking flight existence help and discussing thoughts while the end result is doubtful. Intensivists and different contributors of the extensive care unit will profit drastically from this considerate discussion concerning the emotional, moral, and criminal complexities of creating end-of-life judgements.
Read or Download End-of-Life Communication in the ICU: A Global Perspective PDF
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Heralding serious advancements within the quickly increasing box of healing hypothermia, this reference serves because the first authoritative resource on thermoregulation, physique temperature manipulation, and the implications of hypothermia. members contain well-known leaders and pioneers who've performed a lot of the severe learn within the box.
Surgical Metabolism: The Metabolic Care of the Surgical Patient
This quantity is a complete, state of the art overview for clinicians with an curiosity within the peri-operative dietary administration of all surgical sufferers. The textual content stories common body structure, the pathophysiology of hunger and surgical stressors, and makes a speciality of applicable dietary repletion for numerous universal sickness states.
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This article addresses a number of the questions which happen while doctors of varied disciplines engage and feature diverse plans and interventions, every one with its personal legitimate medical and/or experience-based purpose: Questions related to tourniquet placement, excellent fluids and volumes for resuscitation, VTE prophylaxis and plenty of different administration issues.
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Extra resources for End-of-Life Communication in the ICU: A Global Perspective
Example text
Arch Intern Med 2005;165:1970–1975. M. Teles 2. Paulo Medical Council. Public consultation on the patient's will to refuse extraordinary support measures to prolong life. php. 3. Paulo Medical Council. Public consultation on cases when the physician can refuse invasive support measures and ICU admission for elderly patients. php. 4. Palliative care and end of life policies in Colombia. Available at: http://www. htm 5. ACP-ASIM End-of-Life Care Patient Education Project. Available at: http://www.
Htm. Communicating to Family: The Israeli Perspective Aviel Roy-Shapira Israel is largely an immigrant state. As a result, we have to deal with a large cultural diversity. The predominant Jewish population is divided into several very distinct segments: Ultraorthodox are a small but vocal minority. The moderate orthodox outnumber the former group, but tend to follow their teachings on end-of-life issues. The majority of the Jewish population is nonreligious, but many of these consider themselves traditional.
Incidence and patterns of violent and/or traumatic deaths between 1993 and 1999 in the Transkei region of South Africa. J Trauma 2004;57:125–129. 2. Heyns Adu P, Benjamin RJ, Swanevelder JP, et al. Prevalence of HIV-1 in blood donations following implementation of a structured blood safety policy in South Africa. JAMA 2006;295:519–526. 3. Thiagraj Soobramoney vs. Minister of Health, Province of Kwazulu-Natal, South Africa. Durban Supreme Court Case Number 5846197, August 1997. 4. Language Use and English-Speaking Ability: 2000.


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The Maker community is looking for solutions after an analysis by B.Protocol suggests that it is possible to exploit the liquidation system to create under-collateralized debt.
The researchers created small vaults for $128, just above Maker's "dust" parameter that defines the minimum size for new vaults. As Maker's oracles updated to new prices that made these vaults eligible for liquidation, B.Protocol found that the debt remained unclaimed for several hours.
While the researchers later closed the bad debt loans on their own, the mechanism could be abused to create a Dai position that would never be liquidated. Splitting a $1 million loan in small tranches of slightly more than $100 would cost about $5,000 in gas — a small price to pay for the possibility of completely avoiding liquidation, the analysts assert.
Trending: Bill Barr and Trump Administration Fast-Track New Rule To Allow For Additional Forms of Federal Execution
The reason why these vaults are not liquidated likely has to do with gas prices. Each liquidation process costs approximately 500,000 gas, about 10 times higher than


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Naysayers who claim that CBD oil doesn't work for them are most likely consuming low-high quality CBD oil that actually could not carry any CBD at all. Does CBD oil actually work? Blosum Staff Member 2020-01-17T18:17:fifty nine-08:00Even although the medical group and the FDA haven't recognized CBD oil as an efficient supplement for improved well being, studies are displaying that it does work. It does this by supporting the endocannabinoid system in the physique. This system is the one that regulates a number of others.
Full spectrum CBD oil incorporates a multitude of cannabinoids along with excessive levels of CBD. Our cannabinoid profile incorporates vital levels of secondary cannabinoids, which increases the efficacy of our product. CBD exists in both hemp and marijuana crops. Hemp crops are distinct from the plant strains that produce intoxicating crops.
Comparing Quick Plans In Best Cbd Oil
State laws differ relating to CBD. Many states have legalized Cannabis merchandise or have made particular exceptions for CBD-based mostly merchandise. To know the specifics of your state's laws CBD Oil Edison, test along with your state attorney basic or an lawyer licensed to practice in your state.
The entourage effect is the synergistic interplay of naturally occurring composites present in cannabis. The terpenes, cannabinoids, and flavonoids in hashish work higher when they are consumed together as opposed to used individually from each other. Far-reaching medical claims promote CBD as a natural alternative to the therapy of various medical situations, akin to pain, nervousness, acne, sleep issues, and arthritis.
On this article, we focus solely on CBD which is in its primary, oil type. In spite of everything, it's this oil that is added to all the opposite products yow will discover online. They're not simply MCT oil and CBD. Every is a proprietary blend of vegetable glycerin, sunflower oil, MCT oil, hemp seed oil, and extra.
Many individuals additionally use small doses of cad oil earlier than exercising to enhance their focus and improve muscle endurance so they can go beyond their limits utilizing natural sources. Moreover, CBD oil is also related to some destructive negative effects. In the next part, we'll take a look at some well being dangers related to CBD oil.
Cbd Hemp Oil Secrets – The Options
NuLeaf CBD Oil has gained various consideration. Founded in 2014, this CBD firm discovered its technique to stardom. One of the largest CBD firms and but it doesn't offer a wide selection of merchandise — there are only oils on provide, of various strengths. Nonetheless, plainly investing all of your sources in manufacturing one sort of high-high quality hemp CBD product has actually paid off.
And one of the best part? You do not have to fret about side effects. This 2008 research concluded that CBD is indeed efficient in managing pain without inflicting antagonistic unwanted effects. It is also good for managing insomnia that accompanies the pain.
Examining Clear-Cut Solutions Of Cbd Oils
Cannabinoids are bioactive constituents in hashish crops, and they're primarily what makes cannabis such a precious tool on the planet of pure medication. CBD and THC are cannabinoids, but they're totally different from one another as a result of one will get you excessive (THC), whereas the other won't (CBD).


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Yes to bidets!
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|No response for a subpopulation
How credible should evidence for a composition be? In this case, the opponent argued that the initial analysis of therapeutic efficacy lacked statistical significance. Only a post hoc analysis revealed a significantly better response for a treatment group compared to a placebo group. Moreover, the effect only occurred in a subpopulation of responders, not for the general population. Is one allowed to claim a composition for a general group even if the majority are non-responders, or should one disclaim the non-responders?
Another issue, was the public availability of two documents C30 and C31. C30 was poster and C31 a slide show, both allegedly displayed at a public conference by the proprietor. Both were also included in the IDS statement for a corresponding US patent. Who should prove the public availability in this situation, and what is the appropriate standard?
A related case T 799/16 sharing some of its reasons with the present decision has also been decided.
Reasons for the Decision
2. Sufficiency of disclosure - main request
2.1 The patent in suit seeks to provide a sustained-release oral dosage form of an aminopyridine, most preferably 4-aminopyridine (also called dalfampridine or fampridine), which can be used in the treatment of patients suffering from multiple sclerosis (see paragraphs [0001] and [0009] of the patent in suit and paragraphs [0002] and [0010] of the application as filed).
2.2 The independent claims of the main request specify a dosage regime involving twice-daily treatment with 10 mg of sustained-release aminopyridine, for increasing walking speed. The board considers that the wording of claim 11 does not introduce any limitation not already provided by the term "stable dose treatment" and by the specified dosage of 10 mg bid.
2.3 These claims all relate to a further medical use. According to the established case law of the Boards of Appeal, attaining the claimed therapeutic effect is regarded as a functional technical feature of such claims. In order to meet the requirement of sufficiency of disclosure of Article 83 EPC, the therapeutic efficacy of the composition and dosage regime for the claimed therapeutic indication must therefore be credible.
2.4 It was not in dispute that the person skilled in the art is capable of preparing sustained-release dosage forms of aminopyridines. All objections raised by the appellants with regard to sufficiency concerned the credibility of the alleged therapeutic efficacy. The respondent relied, in this respect, on the data and analysis of a clinical trial (the "MS-F202" trial), as presented in Example 5 of the application as filed.
2.5 Example 5 (see the application as filed, paragraphs [0101] to [0133], and the associated figures) relates to a phase 2, 20-week, double-blind, placebo-controlled treatment study in 206 subjects diagnosed with multiple sclerosis (MS), designed to investigate the safety and efficacy of three dose levels of sustained-release 4-aminopyridine. The dosages administered in this study during a 12-week stable-dose treatment period were 10 mg bid, 15 mg bid and 20 mg bid. The primary efficacy endpoint was an increase, relative to baseline, in walking speed on the "Timed 25 Foot Walk".
2.6 As acknowledged in the application as filed (see paragraph [0079]), it was known that only a proportion of patients, estimated to be about one third, responded to treatment with 4-aminopyridine. The existence of a population of non-responders was also confirmed by the inventors' own results reported in Example 5.
Aminopyridines are potassium channel blockers whose proposed mechanism of action is the restoration of conduction in demyelinated axons. Given the highly variable pathology of MS, only a proportion of MS patients would be expected to possess axons of appropriate functional relevance susceptible to this mechanism of action, which would explain the occurrence of non-responders (see the application as filed, paragraphs [0005] and [0079]).
Contrary to the appellants' view, the existence of non-responders is not a reason to deny sufficiency of disclosure, and the treatment of non-responders does not have to be excluded or disclaimed.
The existence of a substantial proportion of patients who are non-responders is a common phenomenon which is observed with drugs in many treatment areas, such as diabetes, migraine or cancer treatment. It is common practice to treat patients with a drug and change their medication should it turn out that they do not respond to the treatment.
If it can be shown that a relevant proportion of patients benefits from a treatment and that it has acceptable safety, the criterion of sufficiency of disclosure is met since the person skilled in the art has the necessary technical information to perform the treatment.
Therapeutic utility of 10 mg bid 4-aminopyridine ("fampridine")
2.7 As explained in the respondent's reply to the statements setting out the grounds of appeal (section 4) and in document C32 (figures), multiple sclerosis (MS) is a disease that is characterised by unusual variability in the occurrence of symptoms, with frequent episodes of relapse and remission being common. Progression of disability may occur, at variable rates, from onset or from a later stage, with or without plateau or remission phases. As a result of the fluctuating nature of MS symptoms, recognising the clinical benefit of therapies is particularly difficult. This is acknowledged in the application as filed (paragraph [0081]), which states:
"Given the often large variations in function experienced by people with MS, it is difficult for the subject or a trained observer to separate a treatment-related improvement from a disease-related improvement without the element of consistency over time. Consistency of benefit might therefore be expected to be a more selective measure of true treatment effect than magnitude of change".
2.8 According to the respondent, presumably due to these fluctuations, the pre-planned first analysis of the data obtained in the clinical trial of Example 5 for the primary efficacy endpoint (percent change in average walking speed during the 12-week stable-dose period relative to baseline) did not show statistically significant differences between any of the 4-aminopyridine groups and the placebo group (see paragraphs [0103], [0114] and Figure 3 of the application).
That was also the case for a second approach (the "protocol-specified responder analysis"), which identified successful response for each subject as improvement in walking speed (percent change from baseline) of at least 20% (see paragraphs [0104], [0115] and Figure 4 of the application).
2.9 To overcome this difficulty, and following the rationale explained in point 2.7 above, the inventors introduced an adapted evaluation method which focused on the consistency of response rather than the intensity of response to the drug (the post-hoc responder analysis).
This post-hoc analysis identified likely responders as subjects exhibiting a faster walking speed for at least three of five assessment visits during the double-blind stable-dose treatment period as compared with the maximum value observed among a set of five non-treatment visits - four before treatment and one after discontinuation of treatment (paragraph [0105] of the application). Furthermore, the proportions of subjects meeting this criterion in the pooled fampridine groups and in the placebo group were compared.
2.10 This analysis revealed the existence of a subset of subjects who responded to the drug with clinical meaningfulness (paragraph [0120] of the application). The number of subjects who met the post-hoc responder criterion in the pooled fampridine-treated group was 58 (36.7%) versus 4 (8.5%) apparent "responders" in the placebo-treated group, and this difference was statistically significant (p<0.001) (paragraph [0122] and Figure 8). The post-hoc responder rates based on consistency of improved walking speed were significantly higher in all three active-dose groups (35%, 36% and 39%) compared to placebo (9%; p<0006 for each dose group, adjusting for multiple comparisons) (see paragraph [0121] and Figure 7). The mean improvement in walking speed for the fampridine responders was more than 24% (paragraph [0107] and Figure 10). No notable differences in efficacy were found between 15 mg bid and 10 mg bid among responders (see paragraph 0132]). It was also reported that serious adverse effects did not occur in the 10 mg bid group (paragraph [0133]).
2.11 While the appellants, referring to the results summarised in point 2.8 above, disputed that therapeutic efficacy had been demonstrated, the board considers that the explanation for the initial finding of lacking statistical significance, the rationale given for the post-hoc methodology and the respective results presented in Example 5 of the application (see points 2.9 and 2.10 above) are convincing and are also sufficient to have rendered the alleged therapeutic efficacy and safety of 4-aminopyridine at 10 mg bid credible on the effective date of the patent.
Therapeutic efficacy across the scope claimed
2.12 The data presented in the application as filed and the corresponding passages of the patent in suit only relate to 4-aminopyridine, but not to other aminopyridines. Without experimental data it is indeed not possible to ascertain whether the specific dosage of 10 mg bid would be acceptably effective and safe in the case of other aminopyridines. The appellants' already plausible objection in this regard was further substantiated by the findings of document C16, which provides a direct comparison between 4-aminopyridine and 3,4-aminopyridine.
The authors of C16 reported that 4-aminopyridine had a more favourable toxicity profile and was also more effective than 3,4-aminopyridine, including for ambulation (see C16: page 1136, "Results" and "Conclusion"; and page 1139, column 2, lines 1 to 19). While the capsules used according to C16 were immediate-release rather than sustained-release formulations, this does not render the comparison meaningless for the present purpose, since both drugs were administered in immediate-release form and a considerable difference in efficacy was observed. In the studies described in C16, the daily doses of 3,4-aminopyridine were twice as high as the doses of 4-aminopyridine (see C16: second page, "Patients and Methods", last sentence, indicating that identical capsules containing either 5 mg 4-aminopyridine or 10 mg 3,4-aminopyridine were used). The mean daily doses of 4-aminopyridine and 3,4-aminopyridine were 23 mg (range 10 to 35 mg) and 46 mg (range 20 to 70 mg), respectively (see C16: page 1138, column 1, first paragraph).
These are valid reasons why the dosage regime of 10 mg bid cannot simply be extrapolated to further aminopyridines.
2.13 For the reasons set out in point 2.12, the subject-matter of the independent claims of the main request is insufficiently disclosed within the meaning of Article 83 EPC, as far as the scope covering aminopyridines other than 4-aminopyridine is concerned.
5. Admission of documents C30 and C31
5.1 Documents C30 and C31 were filed, for the first time, by appellant-opponent 1 with its statement setting out the grounds of appeal, in conformity with Article 12(1) and (2) RPBA. Pursuant to Article 12(4), second clause, RPBA, these documents are thus, as a rule, to be taken into account in the appeal proceedings.
5.2 Pursuant to Article 12(4), first clause, RPBA, the board has the discretionary power to hold evidence to be inadmissible which could (and should) have been presented in the proceedings at first instance.
5.3 However, the argument that C30 and C31 had been available to the appellants at an earlier time did not constitute a compelling reason for the board to hold these documents inadmissible pursuant to Article 12(4) EPC.
6. Admission of document C27
6.1 The opposition division did not admit late-filed document C27 into the proceedings, since its prior-art status was in dispute and no evidence regarding this issue had been presented by the opponents (see the decision under appeal, point 5 of the Reasons).
6.2 The document was re-submitted by appellant-opponent 1 with its statement setting out the grounds of appeal, in conformity with Article 12(1) and (2) RPBA, together with evidence regarding its publication. In these appeal proceedings, the respondent did not dispute the public availability of C27 on the effective date of the patent and did not maintain the objection against its admission. Hence, the board saw no reason for holding C27 inadmissible pursuant to Article 12(4) RPBA.
7. Public availability of documents C30 and C31
7.1 Relying on documents C30A and C38 (see P308 on pages 25 and 48) inter alia, the appellants contended that the poster C30 and the slide presentation C31 (both undated) had been presented to the public at the 7th Annual Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis and 18th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS) which took place in Baltimore, Maryland (USA) on 18-21 September 2002, i.e. before the effective date of the patent in suit.
7.2 C30 and C31 are identical to references CC15 and CC16 listed in document C30A ("List of References cited by Applicant"), which mentions that these were presented at the ACTRIMS/ECTRIMS conference in September 2002. The respondent itself filed both documents at the US Patent and Trademark Office (USPTO) in 2012 (see C30B and the reply to the statements setting out the grounds of appeal, footnote on page 13), together with the document list C30A, as part of an Information Disclosure Statement (IDS) for the case file of US application number 11/102,559 (see the respondent's letter dated 30 September 2016, point 1.4). The documents were downloaded by appellant-opponent 1 from the USPTO's online register (PAIR).
7.3 The respondent disputed, however, that the content of C30 and C31 was indeed identical to what was presented at the ACTRIMS/ECTRIMS conference.
According to the respondent, these documents had been filed at the USPTO years after the conference in question. At that point in time, it was not known beyond reasonable doubt to the US attorney who wrote C30B (the accompanying letter submitted to the USPTO together with C30A, C30 and C31) whether C30 and C31 really had been presented at the conference of 2002.
As explicitly stated in document C30B, identification of the references in C30A was not meant to be construed as an admission that they were prior art.
Furthermore, C30B included the following statement:
"On information and belief, after reasonable inquiry, the poster and slide presentation listed as References CC15 and CC16, respectively, in the attached List of References Cited, were presented at the ACTRIMS 7th Annual Conference and ECTRIMS 18th Congress on September 18-21, 2002. Applicants reserve the right to correct this information should further information show such correction is warranted."
The respondent also argued that, while there was no evidence from the appellants to show that C30 and C31 were an accurate description of what was disclosed at the ACTRIMS/ECTRIMS conference, the appearance and inaccurate content of C30 and C31 suggested that they were not the visual aids actually used at the conference.
Furthermore, the respondent contended that the presentation of slides or of a poster in both cases also involved an aural element. It could not be established what an audience would have understood in each case in the light of the oral discussion with the presenter.
7.4 It was a disputed subject among the parties what standard of proof was required regarding the public availability of documents C30 and C31.
7.5 According to the case law of the Boards of Appeal, the usual standard of proof is the overall balance of probabilities.
7.6 The stricter standard of proof "beyond all reasonable doubt" has been used, exceptionally, in cases of public prior use where all the supporting evidence lay within the power and knowledge of the opponent. (The issue of public prior presentation of posters or slides has, as a rule, been assessed in line with the requirements for public prior use).
In these appeal proceedings, that condition is not fulfilled since C30 and C31 alleged to be public prior disclosures are the patent proprietor's (respondent's) own documents.
7.7 The respondent also argued that both C30 and C31 involved "ephemeral" oral presentations and that, therefore, the standard of proof for ascertaining the content of the oral disclosure must be higher (see decision T 1212/97, point 2 of the Reasons).
The board considers that, at least in the case of the poster C30, this argument is not convincing, since the disclosure relied on by the appellants is the printed and therefore "fixed" content of the poster displayed, whereas T 1212/97 cited by the respondent deals with the alleged information content of an orally delivered lecture (without a written complement in the form of a script, handout or later publication).
7.8 The question of whether citing a reference in an IDS is, as a matter of principle, an acknowledgement that it is prior art is irrelevant to the issue under discussion. What is more relevant is that the respondent explicitly stated in C30B that to the respondent's best knowledge ("on information and belief and after reasonable inquiry"), C30 and C31 (designated "CC15" and "CC16" in C30A) were presented at the ACTRIMS/ECTRIMS conference of 2002.
7.9 In the case of the poster C30, the respondent's own statement in C30B leaves little room for doubt that this poster was indeed displayed, whereby the entirety of the information printed on the poster was disclosed to the public. In this situation, it was for the respondent to show that this was not the case.
7.9.1 The respondent did not provide first-hand evidence from witnesses, in particular the presenters themselves, regarding the actual printed content of the poster presented at the ACTRIMS/ECTRIMS conference. Instead, the respondent's argument is based on circumstantial evidence. Pointing out certain errors in the technical content of document C30 as well as typographical and formatting errors, the respondent contended that such errors were not expected to occur in a presentation by professional scientists and that the poster therefore could not have been presented in the version shown in C30. C30, retrieved at a later point in time, might simply have been a draft.
7.9.2 This argument is speculative and not persuasive, even less so since it is the respondent itself which should know the exact circumstances. The board also notes that the respondent never retracted its statement in C30B. As a consequence, on the overall balance of probabilities, the poster C30 is considered to form part of the prior art.
7.10 The situation is different in the case of C31, due to C31 being a slide presentation. Slides are typically used as the basis of an oral presentation. No evidence is on file from which it may be inferred that the slides of C31 were handed out in printed form at the conference, or that all of the slides were shown to an audience. There is no evidence regarding the manner or speed of the oral presentation. The printed content of the slides alone is insufficient for establishing what precisely the members of the audience would have understood, and retained, from an oral presentation at the ACTRIMS/ECTRIMS conference during which all or some of the slides of C31 may have been shown. Hence, and irrespective of the standard of proof applied, the content of C31 cannot be considered to be prior art.
This decision T 0421/14 (pdf) has European Case Law Identifier: ECLI:EP:BA:2019:T042114.20190903. The file wrapper can be found here. Photo obtained via PixaBay under the Pixabay license (no changes made).


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