Description

Field of the invention

The invention relates to tobacco- and smokeless prod ^¬ ucts consumable by humans which release nicotinic agonists in ^¬ to a human body in a dose tolerable thereby and which produce effects similar to nicotine released into the body by smoking tobacco .

Background of the invention

A wide variety of tobacco- and smokeless products is known which upon human consumption release nicotinic agonists into a human body in a dose tolerable thereby and which pro ^¬ duce effects similar to nicotine released into the body by smoking tobacco.

The products can be epicurean, non-medical, products used as an indulgence to provide the human body with sensa ^¬ tions similar to that of smoking tobacco, and as an alterna ^¬ tive thereto without any treatment of smoking or nicotine ad ^¬ diction. Examples of such alternatives to smoking tobacco but with less health-related negative side-effects are e.g. e- cigarettes or vaporizers with vaporizing liquids containing nicotine in a suitable form. These release nicotine, without burning, by vaporizing the liquid containing nicotine. The vapour with the nicotine is subsequently inhaled and absorbed in the human body.

However, a disadvantage of the known products is that the human body does not experience a sensation equivalent to that of the nicotine administered to the body by smoking to ^¬ bacco. This in particular when the product is used by a human accustomed to smoking tobacco.

In addition, tobacco- and smokeless medical products are known which are used as part of treating nicotine addic ^¬ tion induced by smoking tobacco. For example, medical prod ^¬ ucts, such as transdermal patches or chewing gum, are known which are used in nicotine replacement therapy, i.e. to admin- ister to the human body nicotine in a gradually lowering dose to treat nicotine addiction. For example, Fiore M.C., Smith S.S., Jorenby D.E., Baker T.B.: "The Effectiveness of the Nic ^¬ otine Patch for Smoking Cessation A Meta-analysis", JAMA.

1994;271 (24) : 1940-1947, describes a nicotine patch. This publication reports that across 17 studies (n=5098 patients) meeting inclusion criteria, overall abstinence rates for the active patch were 27% at the end of treatment and 22% at 6 months. Said differently, the overwhelming majority of pa- tients does not successfully stop smoking.

Thus, the treatments in which these known medical products are used have an unsatisfactory rate of people suc ^¬ ceeding to stop smoking. Summary of the invention

The present invention provides products and methods as described in the accompanying claims.

Specific embodiments of the invention are set forth in the dependent claims.

These and other aspects of the invention will be ap ^¬ parent from and elucidated with reference to the embodiments described hereinafter.

Brief description of the drawings

Further details, aspects and embodiments of the in ^¬ vention will be described, by way of example only, with refer ^¬ ence to the drawings. In the drawings, like reference numbers are used to identify like or functionally similar elements. Elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale.

FIG. 1 schematically shows a cross-sectional view of a transdermal patch.

Detailed description of the preferred embodiments

In the following, details will not be explained in any greater extent than that considered necessary for the understanding and appreciation of the underlying concepts of the present invention and in order not to obfuscate or distract from the teachings of the present invention. The product

The examples hereinafter relate to tobacco- and smoke-less products, e.g. in a form suitable to administer ad ^¬ ditives non-invasively to the human body, such as using the enteral, such as peroral, topical (skin), transmucosal (nasal, buccal/sublingual) or inhalation routes.

For example, the product may be an edible substance, such as chewing gum, either digestible or non-digestible. This allows to provide a tactile buccal sensation in the oral re- gion, and hence a pleasurable sensation to the consumer of the product which can be used to e.g. distract the human brain from the compulsive gestures involved in smoking tobacco prod ^¬ ucts .

Also, the product may be consumable by inhaling, such as a vaporizable liquid, which allows an experience closer to smoking tobacco and also allows to reduce the compulsive de ^¬ sire for smoking. Alternatively, the product may be non- consumable itself but e.g. use transdermal delivery which al ^¬ lows a controlled release without activity of the consumer.

The product comprises a first quantity of a first compound in a form suitable to release in-vivo in a human body a dose of a nicotinic agonist tolerable by the human body and sufficient to provide a sensation similar to that of nicotine released into the body by smoking tobacco. The product further comprises a second quantity of a second compound in a form suitable to release in-vivo in the human body a dose of a non- psychoactive cannabinoid tolerable by the human body which re ^¬ duces the desire to smoke tobacco.

Thus, if the product is a epicurean, non-medical, product the product allows to provide a consumer thereof a sensation more similar to that of nicotine released by smoking because the mental importance of a continuing desire to smoke tobacco at the same time is at least reduced. Accordingly, the product has an enhanced epicurean effect.

Alternatively, if the product is a medical product, e.g. used to treat tobacco smoking addiction, this composition is likely to yield a higher success rate because it at least partially lowers the barrier to successfully quit smoking, which is believed to be caused by continuing mental discom- fort. In particular, the nicotinic agonist allows to reduce the mental discomfort related to a lack of nicotine in the hu ^¬ man body while the non-psychoactive cannabinoid allows to in ^¬ hibit, or at least reduce, the mental discomfort caused by the lack of the habits and emotions the tobacco smoker is addicted to, e.g. cue induced or otherwise related to a craving for smoking tobacco.

The first compound and the second compound can be provided on a common carrier, such a e.g. embedded in a matrix compound or in separate dosing units, e.g. as patches, pills, flasks or otherwise which allow to separately administer the nicotinic agonist and the non-psychoactive cannabinoid to the human body.

The product can be provided in a kit of several prod- ucts, e.g. such as chewing gum, tablets or cartridges of va ^¬ porizer liquid or transdermal patches, with a similar dose of nicotinic agonist and the cannabinoid per product, or with differing doses. The kit can comprise a common package for the products such as a paper- or carboardbox.

For example, the kit can contain at least two prod ^¬ ucts with the quantity of the first compound and/or form of the first compound differing between the products to release different doses of the nicotinic agonist. If the quantities of the first and second compound are on a common carrier, the products may contain the second compound in a quantity and/or form which is the same to release the same dose per product or which differs between the products to release doses of canna ^¬ binoid which differ per product. The kit can comprise in addi ^¬ tion products with only a quantity of the second compound and not the first compound or vice versa.

Non-psychoactive cannabinoid

The non-psychoactive cannabinoid to be released can be any non-psychoactive cannabinoid suitable to reduce the de- sire to smoke tobacco. The non-psychoactive cannabinoid can be selected out the cannabinoids with a metabolic pathway in the human body which differs (at least partially) from a metabolic pathway of tetrahydrocannabinol, to ensure a good inhibition of psychoactive effects. The non-psychoactive cannabinoid can be of a type which acts on a metabolic pathway of endogenous (to the human body) cannabinoid ligands to effectively sup ^¬ press the need to smoke tobacco, and can e.g. be an antagonist to CB1 and/or CB2 receptors in the human body, such as an indirect antagonist of exogenous (to the human body) CB1 and/or CB2 agonists. Without wishing to be bound to theory, it is be ^¬ lieved that a non-psychoactive cannabinoid which increases a concentration in the human body of cannabinoid ligands of CB1 and/or CB2 receptors endogenous to the human body effectively diminishes a craving for nicotine and/or other addictive sub ^¬ stances administered to the human body by smoking tobacco.

The non-psychoactive cannabinoid can be a phytocanna- binoid. Phytocannabinoids are the cannabinoids derived from cannabis plants. Cannabinoids are a group of chemicals known to activate cannabinoid receptors in cells, of which endocan- nabinoids are endogenous cannabinoids found in humans and oth ^¬ er animals and exocannabinoids are exogenous to the human body .

The phytocannabinoids can be isolated from cannabis plants or produced synthetically. When isolating the phytocan ^¬ nabinoids from plants they can be purified to the extent that except for trace quantities thereof all of the other naturally occurring compounds, such as other minor cannabinoids and plant molecules, such as terpenes, are removed. This purifica ^¬ tion results in a purity of greater than 99% (w/w) of the target cannabinoid.

The phytocannabinoid can be in the form of a botani ^¬ cal drug substance (BDS) . A "botanical drug substance" or "BDS" is defined in the Guidance for Industry Botanical Drug Products Draft Guidance, August 2000, US Department of Health and Human Services, Food and Drug Administration Centre for Drug Evaluation and Research as:

"Λ drug derived from one or more plants, algae, or microscopic fungi. It is prepared from botanical raw materials by one or more of the following processes : pulverisation, decoction, ex ^¬ pression, aqueous extraction, ethanolic extraction or other similar processes."

A botanical drug substance does not include a highly purified or chemically modified substance derived from natural sources. Thus, BDS derived from cannabis plants do not include highly purified pharmacopoeial grade cannabinoids and will containe a principle phytocannabinoid and other phytocanna- binoids .

The "principle phytocannabinoid" in a BDS is the phy- tocannabinoid that is present in an amount that is higher than that of the other phytocannabinoids . The product can comprise BDS with a non-psychoactive cannabinoid as the principle phy ^¬ tocannabinoid present in an amount greater than 40% (w/w) of the total extract. More preferably the principle phytocanna ^¬ binoid is present in an amount greater than 50% (w/w) of the total extract. More preferably still the principle phytocanna ^¬ binoid is present in an amount greater than 60% (w/w) of the total extract.

The amount of the principle phytocannabinoid in the

BDS is preferably greater than 75% of the phytocannabinoid- containing fraction, more preferably still greater than 85% of the phytocannabinoid-containing fraction, and more preferably still greater than 95% of the phytocannabinoid-containing fraction.

Preferably, the BDS has a THC content below the Low- est Observed Effect threshold, such as less than 0.3% w/w, more preferably less than 0.2% w/w (measured in accordance with annex C to European Directive 1164/89) . This is generally considered to be non-psychotropic and allows a product which is safe as a product. Generally speaking it is advantageous is if the content of psycho-active cannabinoids in the product is below the regulatory threshold, and for practical purposes negligible .

The non-psychoactive cannabinoid can for example by cannabidiol, also referred to as CBD ( 2- [ ( 1R, 6R) -3-methyl- 6- (prop-l-en-2-yl ) cyclohex-2-en-l-yl ] -5-pentylbenzene-l , 3-diol) , which has the following structural formula:

Mechoulam, L. Hanus, "Cannabidiol: an overview of some chemical and pharmacological aspects, art I: chemical aspects", Chemistry and Physics of Lipids, 121 (2002) 35-43 describes the synthesis of CBD. The product may e.g. comprise a natural ^¬ ly occurring CBD isomer, such as A ¹ -cannabidiol .

In Morgan et all, "Cannabidiol reduces cigarette con ^¬ sumption in tobacco smokers: Preliminary findings", Addictive Behaviors, Volume 38, Issue 9, Pages 2433-2436, a treatment with CBD (as aerosol with an inhaler administered a dose of 400 \iq CBD dissolved in absolute ethanol ¾5%) has been found to be particularly effective in reducing the number of cigarettes smoked with 40%.

The cannabinoid may also be a synthetic derivative of CBD, such as CBD-DMH (CBD di-methylheptyl ) , although other cannabinoids can be used as well.

Nicotinic agonist

The nicotinic agonist to be released can be any type of nicotinic agonist suitable to substitute for nicotine re ^¬ leased into the body by smoking tobacco. The agonist can be a full agonist or a partial agonist. A suitable compound has found to be nicotine, 3- [ (2S) -l-methylpyrrolidine-2- yl] pyridine, with the following chemical structure:

For example, the nicotinic agonist may be nicotine in its nat ^¬ urally occurring form: (-) -nicotine . The nutritive product

The product can be a non-medical product, e.g. a nu ^¬ tritional supplement which contains the first compound and the second compound in a biologically acceptable form. In such a case, the product can contain the cannabinoid as a BDS and nicotinic agonist in a non-prophylactic form. For example, the product may be a chewing gum or other orally consumable prod ^¬ uct comprising an edible, e.g. digestable or indigestible, carrier matrix in which the nicotinic agonist and the canna- binoid are embedded in a suitable form, e.g. as a salt, and which are released upon consumption e.g. by chewing or swallowing. The product may also be vaporizable or other form to be inhaled and e.g. comprise a vaporizable carrier in which the compounds are dissolved, such as a product where nicotinic agonist and the cannabinoid are dissolved in a suitable vapor- izable liquid or gel.

The medical product

In the medical product, the substances used can be of a pharmacopeal grade. In this example, the product comprises the first compound in a pharmaceutically acceptable form suit ^¬ able to release a dose of nicotinic agonist tolerable by the human body and effective to treat symptoms of a nicotine defi ^¬ ciency in the body induced by the human body being deprived from smoking tobacco, and the second compound is in a pharma- ceutically acceptable form suitable to release in-vivo in the human body a dose of non-psychoactive cannabinoid tolerable by the human body and effective to treat a craving for smoking tobacco .

In a first example, the product is a transdermal patch which can be is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. The transdermal patch allows a controlled release of the nico ^¬ tinic agonist and the cannabinoid into the human body. The patch may e.g. comprise a porous membrane covering a first reservoir with the nicotinic agonist, or precursor, thereof in a pharmaceutically acceptable form and a second reservoir with the cannabinoid, or a precursor thereof, in a pharmaceutically acceptable form.

Referring to FIG. 1, there is shown a cross-sectional view of the first example, which is a transdermal patch 10.

The patch 10 comprises a wall, or backing layer, 12 with a top face portion 26. The wall 12 provides a reservoir 14 having an open bottom end 15 and an opposing top end 17. The wall 12 can be composed of a medically approved plastic material including plastic composites formed by any suitable technique. Other suitable materials, generally of plastic polymeric composi ^¬ tion, can be used for the wall 12 and are known.

The reservoir 14 includes a matrix 20 capable of sus- pending a drug for subsequent release. Suitable formulations are e.g. guar, acacia, or xanathan gum, or a gelling agent or polymer such as carboxypolymethylene, hydroxyethylcellulose or polyacrylamide . The matrix 20 includes a first region 20 a and a second region 20 b located at the top end 17 of the reser- voir 14. The first and second regions 20 a and 20 b can be composed of the same material or different materials exhibit ^¬ ing different diffusion rates and/or chemical properties.

First region 20a thus forms a first reservoir for the first compound, and second region 20b thus forms a second reservoir for the second compound. The sensitivity of the matrix materi ^¬ al to the permeation of moisture is controlled by the choice of materials or formulation. The matrix 20 is designed to al ^¬ low moisture, ions, electrolytes and the like, typically, pre ^¬ sent in perspiration, to diffuse or permeate in order to re- lease the substances for delivery to, and subsequent passage through the skin.

In the example, the first region 20a of the matrix 20 comprises the nicotinic agonist 21, or a precursor thereof, suspended therein. The second region 20b of the matrix 20 com- prises the non-psychoactive cannabinoid, or a precursor there ^¬ of, suspended therein. In both regions, the substances are in a pharmaceutically acceptable form. The first and second ma ^¬ trix regions 20a and 20b can be suitably formulated and posi ^¬ tioned with one another to provide rates and times of delivery as desired.

The matrix 20 is maintained in contact with the pa ^¬ tient's skin during administration via a permeable adhesive layer 16. The permeable adhesive layer 16 can be composed of a suitable pressure-sensitive adhesive material, and is located at the bottom end 15 of the reservoir 14 overlaying the bottom portion of the matrix 20. The adhesive layer 16 enables the matrix 20 and the wall 12 to be secured to the skin of the pa ^¬ tient, while permitting free passage of molecules (e.g. per ^¬ spiration and drugs) in between the patch 10 and the patient's skin. It will be understood that when the patch 10 is provided to the patient, the adhesive layer 16 is normally covered with a disposable protective layer 18 that the patient must remove prior to application. When attached to the skin of the pa- tient, the wall 12 provides an occlusive covering, which en ^¬ hances hydration of the skin area covered by the patch 10, and diffusion of the perspiration into the matrix 20. Hydration of the skin fosters release and absorption of the first and sec ^¬ ond compounds. Alternatively, substantial portions of the ad- hesive layer 16 can be removed or eliminated to provide direct contact of the matrix 20 with the patient's skin for enhancing ease of delivery of the substances into the human body.

The material of the matrix regions 20 a and 20 b can be selected or formulated to control of the rate of drug re- lease from the matrix 20, as well as the diffusion rate of the perspiration through which the corresponding matrix regions 20 a and 20 b are activated for release of their associated phar ^¬ maceutical agent such as agonist 21 and cannabinoid 23, re ^¬ spectively. The matrix regions 20 a or 20 b can be formulated to be relatively impervious to moisture, for example, one that is thicker or less permeable because of its physico-chemical properties, or one that contains a higher content of hydropho ^¬ bic elements in its composition, will result in a more gradual drug release over a sustained time period and gradual diffu- sion of the patient's perspiration there through. In contrast, a matrix region 20 a or 20 b that is relatively permeable to water will rapidly release the drug over a relatively shorter time period.

Once the patch 10 is properly applied to the pa- tient 's skin, the occlusive wall 12 entraps the patient's per ^¬ spiration produced from the covered area of the skin. The per ^¬ spiration permeates through the adhesive layer 16 into the first matrix region 20 a and the second matrix 20b. As the perspiration solvates the matrix material, the suspended ago- nist 21 is released and flows to the patient's skin for deliv ^¬ ery. As the perspiration flows into the second matrix region 20 b, the cannabinoid 23 is released therefrom and begins to diffuse through the matrix 20 toward the patient's skin. The transdermal patch 10, as described previously, includes the matrix 20 with two regions 20 a and 20 b, each exhibiting individual diffusion characteristics. The matrix 20 urges the nicotinic agonist 21 and the cannabinoid 23 to con- trolled flow towards the patient's skin based on the concen ^¬ tration gradient. Similarly, the perspiration including moisture, ions, electrolytes and other secretions, produced by the patient, flow into the matrix 20.

Thus, when applied to the skin, the patch delivers a steady dose of nicotinic agonist and cannabinoid over a pro ^¬ longed period of time, e.g. 12, 24 or 48-hours. By using a se ^¬ ries of patches over a period of time, such as several weeks, with the dose of nicotinic agonists per patch lowering in time, e.g. per patch or for a sequence of patches, the nico- tine dose can be reduced gradually until the patient no longer craves for nicotine and/or smoking tobacco, and they can stop using the medication. The patient can choose to continue using a maintenance dose of CBD as needed if they choose to do so using other delivery methods. In this respect, the dose of CBD per patch may remain constant over time or vary over time.

The medical product may likewise use another delivery mechanism and for example be an inhaler which contains a biologically acceptable inhalable aerosol or powder to be inhaled by the patient which acts as a carrier for the first compound and the second compound. In such as case the first compound can be the free-base nicotinic agonist or a precursor thereof and the second compound be the cannabinoid or a precursor.

Also, the medical product can e.g. be chewing gum or a digestible product, with a digestible or indigestible gum base as matrix in which the first compound and/or the second compound are embedded and which are released by e.g. chewing or digesting of the gum base. In such, a suitable form of the first compound can be the nicotinic agonist or a precursor thereof can be in free-base form or as a salt and the second compound be the cannabinoid or a precursor.

The quantities of the first compound and the second compound in the products may be such that they can be used in the following dosage forms & strengths may be as follows:

7 mg nicotine and 10 mg CBD per 24 hours; 14 mg nicotine and 10 mg CBD per 24 hours;

21 mg day nicotine and 10 mg CBD per 24 hours.

For instance, in case the product are individual transdermal patches, each patch may contain the amount to be released in 24 hours. However, it will be apparent that the units may e.g. be administered in a different rhythm, for ex ^¬ ample 1 per 12 hours or otherwise and that therefore the amount of substance be adjusted proportionally.

Smoking Cessation program

The medical products described can be used to treat tobacco smoking addiction. Such a treatment can comprise ad ^¬ ministering a nicotinic agonist, or precursor thereof, in a form suitable to release in-vivo in a human body a dose toler ^¬ able by the human body and effective as a treatment to symp ^¬ toms of the nicotine deficiency in the body induced by the hu ^¬ man body being deprived from smoking tobacco; and a non- psychoactive cannabinoid, or precursor thereof, in a form suitable to release in-vivo in the human body a dose tolerable by the human body and effective as a treatment of a craving to smoke tobacco.

It is proposed that the initial dosage is, inter alia, based on how heavily the patient smoked, e.g. in number of cigarettes or equivalent measures. This will provide an in ^¬ itial adequate replacement for the nicotine consumed by smok ^¬ ing tobacco. The initial dose and duration of therapy can de ^¬ pend on a number of factors such as weight, number of ciga ^¬ rettes smoked, and various medical conditions. For example, the dosage can range from 7 mg to 21 mg of nicotinic agonist administered to the patient's body.

In this example, the dosage is lowered over time to allow the body to gradually adjust to less nicotine and can step down to a lower strength until the patient is gradually able to taper off the nicotine replacement patches altogether. As the cannabinoid, in particular CBD, is not addictive but highly effective for stress reduction, a common cause for relapse, the use thereof can be continued even after the nico ^¬ tine is out of the system. Therapy for most people will begin with one 21 mg nicotine and 10 mg CBD patch per day for 6 weeks. The next stage of therapy will gradually reduce the dose of nicotine but the CBD dose will remain at 10 mg.

After successful completion of the first 6-week stage, the 14 mg nicotine and lOmg CBD patch is started for 2 weeks, immediately followed by the 7 mg/day patch for another 2 weeks. Treatment will generally take 8 to 12 weeks. The med ^¬ ication may e.g. be taken for 3 months or less. The patient has to stop smoking completely when taking this medication.

Although other dosing regimens may be found to be suitable, it is proposed that the following treatment be used, in which the dosing depends on the number of cigarettes (or cigarette equivalents) smoked per day before the treatment as follows :

20 or more cigarettes/day - 21/14/7-mg regimen:

21-mg nicotine+ 10 mg CBD per 24 hours for 6 weeks, 14-mg nicotine + lOmg CBD per 24 hours for 2 weeks, 7-mg nicotine +10 mg CBD per 24 hours for 2 weeks.

10 or more cigarettes/day- 14/7-mg regimen:

14-mg nicotine+ 10 mg CBD per 24 hours for 6 weeks, 7-mg nicotine + 10 mg CBD per 24 hours for 2 weeks.

The dose may e.g. be provided through a transdermal patch or other controlled release mechanism to ensure a gradu ^¬ al release over the 24 hours. However, any other suitable med ^¬ ical product such described above may be used to deliver the treatment .

In the foregoing specification, the invention has been described with reference to specific examples of embodi ^¬ ments of the invention. It will, however, be evident that various modifications and changes may be made therein without de ^¬ parting from the broader scope of the invention as set forth in the appended claims.

For instance, although in the examples nicotine is use as a suitable nicotinic agonist, it will be apparent that other full or partial nicotinic agonists, such as varenicline, may be used. Also, pharmaceutically acceptable derivatives, such as salts, resins and complexes, of the nicotinic agonist and/or the non-psychoactive cannabinoid may be used as a pre ^¬ cursor thereof. For example, nicotine salts such as nicotine bitartrate, nicotine hydrochloride, nicotine dihydrochloride or nicotine sulfate, or other nicotine actives may be used. Also, although CBD is described as an example of a non- psychoactive cannabinoid in the examples, other non- psychoactive exogenous cannabinoids may be used.

Furthermore, although in some examples the product only contains a single cannabinoid it will be apparent that the product may comprise several cannabinoids without the product itself exhibiting noticeable psychoactivity, e.g. by containing trace quantities of psychoactive cannabinoids, such as when the cannabinoid is a botanical drug substance with non-psychoactive cannabinoids as principle phytocannabinoid .

Furthermore, the medical product may also be e.g. a chewing gum or a vaporizer liquid which contains the nicotinic agonist and the non-psychoactive cannabinoid. For example, the vaporizer liquid may comprise glycerine, water and the nico ^¬ tinic agonist and the non-psychoactive cannabinoid, and may further comprise propylene glycol and additional substances such as flavourings.

However, other modifications, variations and alterna- tives are also possible. The specifications and drawings are, accordingly, to be regarded in an illustrative rather than in a restrictive sense.

In the claims, any reference signs placed between pa ^¬ rentheses shall not be construed as limiting the claim. The word Comprising' does not exclude the presence of other ele ^¬ ments or steps then those listed in a claim. Furthermore, the terms "a" or "an, " as used herein, are defined as one or more than one .

Also, the use of introductory phrases such as "at least one" and "one or more" in the claims should not be con ^¬ strued to imply that the introduction of another claim element by the indefinite articles "a" or "an" limits any particular claim containing such introduced claim element to inventions containing only one such element, even when the same claim in- eludes the introductory phrases "one or more" or "at least one" and indefinite articles such as "a" or "an." The same holds true for the use of definite articles. Unless stated otherwise, terms such as "first" and "second" are used to ar- bitrarily distinguish between the elements such terms describe. Thus, these terms are not necessarily intended to in ^¬ dicate temporal or other prioritization of such elements The mere fact that certain measures are recited in mutually dif ^¬ ferent claims does not indicate that a combination of these measures cannot be used to advantage.