Photosensitizers for use for the treatment of viral infections in dairy cattle and in methods for controlling infectious agents on milking equipment

Abstract

The present invention relates to the treatment of viral infections using photosensitizers in dairy cattle. The invention also relates to the prevention of transmission of viral infections from dairy cattle infected by virus to the same or other species. The invention is also directed to methods of controlling infectious agents on milking equipment for dairy cattle. The invention is further directed to milking processes including the treatment of viral infections and / or the prevention of transmission of viral infections from dairy cattle infected by virus to the same or other species and / or the methods for controlling infectious agents on milking equipment for dairy cattle.

Description

[0001] Habermann, Hruschka & Schnabel

[0002] Patentanwalte • European Patent and Trade Mark Attorneys

[0003] Our ref.: Date

[0004] P 2156 WO 4 August 2025

[0005] Applicants:

[0006] Dr. Jochen Arentz Rondeel 27 22301 Hamburg / DE

[0007] Dr. Hans Albrecht Ammerstrasse 9A 81479 Munchen / DE

[0008] Use of photosensitizers for treatment of viral infections in dairy cattle and in methods for controlling infectious agents on milking equipment

[0009] The present invention relates to the treatment of viral infections using photosensitizers in dairy cattle. The invention also relates to the prevention of transmission of viral infections from dairy cattle infected by virus to the same or other species. The invention is also directed to methods of controlling infectious agents on milking equipment for dairy cattle. The invention is further directed to milking processes including the treatment of viral infections and / or the prevention of transmission of viral infections from dairy cattle infected by virus to the same or other species and / or the methods for controlling infectious agents on milking equipment for dairy cattle.

[0010] Photosensitizers have been used for photodynamic therapy (PDT) of infections by bacteria and fungi as well as cancer and tumours. Photosensitizers are generally dyes which are transferred to a higher energetically state by absorption of light typically in the visible wavelength range. In the photo-activated state the photosensitizer is able to transfer, as a donor, at least part of the energy to an acceptor molecule. For application in PDT, the energy transfer leads, at least in part, to reactive oxygen species (ROS) such as the superoxide radical which in turn damages various cellular components, especially the cell membrane, of the target cells such as tumour cells, bacteria, or fungal cells, by redox reactions. PDT is mostly applied through local application of the dye and light typically emitted by monochromatic and / or coherent light sources.

[0011] EP 3943110 A1 discloses the use of PDT for the treatment of viral respiratory infections, in particular coronaviruses.

[0012] Several publications (e.g. Combuca da Silva Junior et al. (2023) Photodiagnosis and Photodynamic Therapy 42, 103337) describe the prevention or treatment of bovine bacterial mastitis using antimicrobial PDT applied to the teats as a post-dipping (i.e. , post-milking) procedure. Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys

[0013] In the Spring of 2024, an outbreak of avian influenza virus (H5N1) infections in bovine herds in the U.S.A, has occurred (Eisfeld et al. (8 July 2024) Nature https: / / doi.org / 10.1038 / s41586- 024-07766-6). This avian flu outbreak in bovine cattle, given the high number of potentially infected animals often held in large herds in combination with the considerable number of contacts to humans and, importantly, a potential spreading of virus via dairy products stemming from infected - but yet unrecognized as being infected - cows could impose a substantial risk of transmission of avian flu, but also other viruses, to humans threatening a potentially global zoonosis.

[0014] There is an urgent need for safe and effective regimen for treatment and prevention of viral infections in dairy cattle, in particular cows. Importantly, such regimen should effectively control and optimally prevent further transmission of viruses that may eventually be able to infect humans.

[0015] The technical problem underlying the present invention is to provide improved treatment of viral infections in dairy cattle.

[0016] The solution to the above technical problem is provided by the embodiments of the present invention a characterised in present description and the appended claims.

[0017] In particular, the present invention provides, under a first aspect, the use of at least one photosensitizer in the treatment and / or prevention of viral infections in dairy cattle wherein the photosensitizer is at least applied to at least a part of the udder of the animal wherein the at least part of the udder includes one or more, preferably all, teats. Preferably, the photosensitizer is applied to the one or more, more preferably, preferably all teats of the animal. More preferably, the teat(s) is / are the substantially only part where the photosensitizer is applied to.

[0018] Under a further aspect, the invention is directed to the use of at least one photosensitizer as outlined herein in the prevention of transmission of a virus from infected dairy cattle, most preferably infected bovine cattle, to a different species such as a human. Thus, the invention is also directed to the use of at least one photosensitizer as outlined herein in the prevention of a zoonosis from virus-infected dairy cattle, most preferably virus-infected bovine cattle. The present invention further provides the use of at least one photosensitiser as outlined herein for the prevention from entering into the milk taken from the dairy cattle during a milking process, or at least for the reduction of the number of live viruses, preferably of infectious viruses, entering into the milk taken from the dairy cattle during a milking process Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys compared to the number of viruses entering from the milk taken from an untreated, preferably untreated and infected, dairy cattle. Preferably, the number of live viruses, preferably of infectious viruses, entering into the milk taken from the dairy cattle during a milking process is reduced by at least about 50 %, more preferably by at least about 60 %, yet more preferred by at least about 70 %, even more preferred by at least about 80 %, still more preferred by at least about 90 %, most preferably by at least about 95 %, compared to the number of viruses entering from the milk taken from an untreated, preferably untreated and infected, dairy cattle.

[0019] Viral infections of dairy cattle are preferably detected by PCR on material taken from the dairy cattle, preferably from nasal mucosa and / or oral mucosa and / or teat(s) (the letter being particularly preferred), for example by nasal swab, oral swab or teat swab, with teat swab being particularly preferred.

[0020] It is understood according to the invention that the term ’’treating" or “treatment" means that the severity of the condition such as mastitis, fever, subnormal feeding behavior and / or subnormal movement behavior, induced by a viral infection in dairy cattle, preferably bovine dairy cattle, preferably a condition such as those mentioned above caused by an influenza virus, more preferred an avian influenza virus such as an influenza virus of a subtype selected from H5, H7 and H9 influenza virus, particularly preferred an influenza virus selected from the subtypes selected from the subtypes H5N1, H7N9, H5N6 and H9N2, does at least not progress as compared to the non-treated condition, preferably the severity of the condition does not progress, more preferably, the severity of the condition is lessened, even more preferred substantially lessened, and, ideally, the condition is cured to a substantial extent. Preferably, the severity of the condition according to the invention is reduced at least by 30 %, more preferably by at least 50 %, particularly by at least 70 %, even more preferred by at least 90 %, with complete cure of the condition being the most preferred outcome of the inventive treatment. In preferred embodiments of the invention, the treatment results in a state where the animal is incapable of further transmitting the virus, preferably influenza virus, more preferred an avian influenza virus such as an influenza virus of a subtype selected from H5, H7 and H9 influenza virus, particularly preferred an influenza virus selected from the subtypes selected from the subtypes H5N1, H7N9, H5N6 and H9N, to other subjects such as other animals of the same species or a different species such as a human. Such a non-transmissible state is typically reached when a viral PCR test, preferably a PCR test for an influenza virus, more preferred an avian influenza virus such as an influenza virus of a subtype selected from H5, H7 and H9 influenza virus, particularly preferred an influenza virus selected from the subtypes selected from the subtypes H5N1, Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys

[0021] H7N9, H5N6 and H9N, of material taken from the nasal mucosa and / or oral mucosa and / or throat mucosa and / or teat of the animal shows no detectable threshold signal after at least about 33, 34 or 35 PCR cycles.

[0022] The term “prevention” as used in the context of the present invention typically relates to a prophylactic treatment of a dairy cattle, most preferred bovine dairy cattle, against viral infections. Preferably, prevention means that the animal concerned preferably does not show any signs or at least shows a lesser degree of signs of a viral infection such as mastitis and / or fever and / or subnormal feeding behavior and / or subnormal movement behavior, preferably infections of influenza viruses, more preferred avian influenza virus such as an influenza virus of a subtype selected from H5, H7 and H9 influenza virus, particularly preferred an influenza virus selected from the subtypes H5N1, H7N9, H5N6 and H9N2Jn other embodiments, prevention means that an animal over the treatment period and preferably at least about 1 week to about 8 weeks thereafter shows no viral infection as evidenced by a negative viral PCR test,

[0023] In the context of the use of the at least one photosensitizer as outlined herein for the prevention of transmission of viruses from dairy cattle to a different species such a human, the term “prevention” preferably relates to a state that the use of the at least one photosensitizer prevents the transmission to the different species such as human to an extent that a viral infection having or having had contact with a dairy cattle itself or with a dairy product such as milk from a dairy cattle is essentially not measurable. _Such a state is typically reached when a viral PCR test, preferably a PCR test for an influenza virus, more preferred an avian influenza virus such as an influenza virus of a subtype selected from H5, H7 and H9 influenza virus, particularly preferred an influenza virus selected from the subtypes selected from the subtypes H5N1 , H7N9, H5N6 and H9N, of material taken from the nasal mucosa and / or oral mucosa and / or throat mucosa and / or teat of an animal of a different species, or of material taken from the nasal mucosa and / or throat mucosa of a human shows no detectable threshold signal after at least about 33, 34 or 35 PCR cycles

[0024] Dairy cattle according to the invention relates to female mammals producing milk which is used for making dairy products. Preferably, the invention provides the inventive treatment, including preventive treatment, for bovine diary cattle, sheep, goats, horses, water buffaloes and camelids. Camelids according to the invention include dromedary camels, Bactrian camels, wild Bactrian camels, lamas, alpacas, vicunas, and guanacos. It is understood according to the invention that the above term “dairy cattle” as well as the above-described Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys preferred species terms refer to the respective female animal, more preferably the domestic female animal.

[0025] The photosensitizer, in preferred embodiments present in a solution as further outlined in more detail below, may be applied by a spraying or nebulizing device. In preferred embodiments of the invention the spraying or nebulizing device is integrated in or is connected to or forms a part of, a teat cup device.

[0026] A teat cup device according to the invention is a device typically having a conical form which has an upper opening for receiving at least part of the teat, said part at least comprising the tip of the teat, more preferably essentially the complete teat. The inner wall of a teat cup device is preferably shaped as an essentially negative of the form of the teat. The inner wall of the teat cup may comprise a liner of a soft material such as soft plastic or rubber which may be of natural rubber or synthetic rubber. In one embodiment, the teat cup device may be connected to a spraying device such as a dip sprayer or of dip nebulizer wherein the dip sprayer or dip nebulizer is connected to the lower or lowest part of the teat cup via a tubing or duct through which the sprayed or nebulized, respectively, photosensitizer is delivered by applying pressure to the sprayer or nebulizer part of the device, e.g. by pumping means, to the teat cup which comprises one or more holes being in connection with the tubing or duct, respectively, such that the photosensitizer enters the inner part of the teat cup and is applied to the teat. The present invention is also directed to a teat cup device comprising one or more teat cups connected to a spraying device, preferably a dip sprayer or dip nebulizer wherein the dip sprayer or dip nebulizer comprises a container or reservoir containing at least one photosensitizer, preferably a solution thereof, as outlined herein below.

[0027] The teat cup device of the invention can also comprise more than one teat cup, preferably two or four teat cups depending on the number of teats of the dairy cattle. The number of teat cups matching the number of teats of the dairy cattle are preferentially designed such that a tubing or duct as described before for a device for one teat connects each teat cup with a collective spraying or nebulizing device. In this manner, the teat cup device may take the form of a device resembling a milking cluster (the device being herein also referred to „photosensitizer application cluster device") with the adequate number of teat cups, preferably two or four, matching the number of teats of the diary cattle question, and tubing or ducts for transporting the photosensitive or solution or suspension thereof to the at least the bottom of each teat cup for delivering the photosensitizer or solution or suspension thereof though an inner opening of the teat cup into the teat cup. In preferred embodiments, the photosensitizer application cluster device is connected via the tubing or ducts leading to Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys the teat cups to a photosensitizer container or reservoir, respectively, preferably a pressurized container / reservoir or at least a container / reservoir that comprises means for pressurizing the container / reservoir or means for pumping the photosensitizer or solution or suspension thereof via the tubing or ducts to the teat cups as outlined above,

[0028] For bovine cattle, water buffalo and camelids treated according to the invention, the number of teats preferably treated is four, whereas for goats, sheep and horses treated according to the number of teats preferably treated is two.

[0029] Therefore, the number of teat cups of the teat cup device is preferentially four when bovine cattle or camelids is / are treated according to the invention, whereas the number of teat cups of the teat cup device is preferably two when sheep, goats or horses are treated according to the invention.

[0030] In preferred embodiments of the invention, the inventive use and treatments are carried out as steps in the context of or as steps of, respectively, the milking process.

[0031] Previous methods for treatment of microbial mastitis in bovine cattle using PDT apply the procedure after milking, in particular after the typically carried out dipping process (= post dipping) during which the teats of the cattle are cleaned and, optionally, disinfected, after milking.

[0032] Especially for preventing (further) transmission of viruses spread by dairy cattle, the inventive use of photosensitizers as well as the inventive treatment methods, including application of the at least one photosensitizer to at least a part of the udder and, most preferably, irradiating the at least part of the udder with light causing the photosensitizer to be transferred to an active state, is applied at least before milking, i.e. pre-dipping. In other preferred embodiments, the inventive use and treatments are applied post milking. In still further preferred embodiments of the inventive use and treatments are applied pre milking and post milking. According to the invention, the terms “pre-milking / pre-dipping” and “post- milking / post-dipping”, respectively, preferably relate to the sequence of steps typically occurring before (pre-milking / pre-dipping) or after (post milking / post dipping) the actual milking step. In preferred embodiments of the invention, the application of the photosensitizer, most preferred followed by the irradiation, to the at least part of the udder as outlined herein is carried out directly before the actual milking step, preferably after teat stimulation. In other embodiments of the invention, the application of the photosensitizer, most preferred followed by the irradiation, to the at least part of the udder as outlined herein Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys is carried out before a washing and / or disinfection step preceding the actual milking step. In further preferred embodiments of the invention, a washing and / or disinfection step is carried out between the application of the photosensitizer, most preferred followed by the irradiation, and the actual milking step, which may be before or after teat stimulation. For avoidance of doubt, the washing and / or disinfection step(s) referred to in the preceding sentence are in any case preceding the application of the photosensitize and, optionally, the irradiation step.

[0033] Additionally, the photosensitizer may, in certain embodiments of the invention, be applied to the respiratory tract of the animal.

[0034] For applying the photosensitizer at the required amount and concentration to the respiratory tract of the cattle, it is preferred that the photosensitizer is applied inra-nasally and / or intra- orally and / or intra-pharyngeally.

[0035] As mentioned above, the photosensitizer needs to be activated in order to exert its function of at least damaging or, optimally, eliminating viruses infecting the animal to be treated, which is accomplished by light emission on the part or region of the animal in need of the inventive treatment where the photosensitizer has been applied to.

[0036] Thus, it is preferred that the treatment comprises irradiating at least a part of the udder of the animal wherein the at least part of the udder includes one or more, preferably all, teats with light comprising or having a wavelength causing the photosensitizer to be transferred to an active state. Also in connection with the irradiation aspect of the invention, the above definitions and preferred embodiments relating to the application of the photosensitizer apply.

[0037] In preferred embodiments of the invention comprising application of the at least one photosensitizer to the respiratory tract of the cattle, the light emission is directed to the respiratory tract, or at least a part thereof, of the animal.

[0038] The light for irradiating at least a part of the udder of the animal, and optionally as outlined above, at least a part of the respiratory tract has a wavelength, or at least comprises a wavelength, and typically also an intensity, preferably in terms of energy density, i.e. applied energy per surface area, causing the photosensitizer to be transferred to an active state as outlined above.

[0039] In certain embodiments of the invention the treatment comprises irradiating at least a part of the respiratory tract of an animal from outside of the animal with light comprising or having a Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys wavelength causing the photosensitizer to be transferred to an active state. It is conceived that one or more different parts of the respiratory tract may be irradiated one or more times for a time effective to provide the sufficient light energy so as to effect the inventive transfer of the photosensitizer, in particular the effective amount administered to the respiratory tract, or one or more parts thereof, to the active state at least in the irradiated part or region, or whole of, respectively, of the respiratory tract. Parts of the respiratory tract which may be conveniently irradiated from the outside of the animals body include, e.g. nose, mouth (preferably, the animal’s mouth can be irradiated while in the opened or at least partially opened state), cheeks (one side or both sides, preferably left and right cheek simultaneously or sequentially), neck, throat, chest and / or back of the animal to be treated. It is to be understood that the term “from the outside of the animal’s body” means that the irradiation is directed to the skin of the animal in the respective area, in the following also denoted as “transcutaneous irradiation”, with two exceptions, namely, the mouth and the nose: as outlined before, the mouth of the animal can be irradiated in an open state where the emitted light will also, or mainly, irradiate the oro-pharyngeal part of the respiratory tract of the treated animal. The nose of the animal can also be treated by emitting light into the nostrils of the animal so that the light also, or mainly, reaches the nasal part of the animal’s respiratory tract. In any case, however, irradiation from the outside of the animal’s body means that the light-emitting device is not introduced into any parts of the respiratory tract.

[0040] In other preferred embodiments of the invention wherein additionally at least a part of the respiratory tract of the animal in need of the inventive treatment is irradiated within the animal’s body, preferably by using a light source which is introduced into the infected or at least suspected to be infected animal. In an embodiment thereof, the light source is equipped with fibre optical elements, e.g. a waveguide, dimensioned, in particular with respect to its diameter and length, to be introduced intra-nasally and / or intra-orally into the animal’s respiratory tract and pushed to the desired site of light emittance or irradiation, respectively. The irradiation of the animal from inside the body, preferably via suitable fibre optics, can be directed to one or more desired parts of the inner respiratory tract such as intra-nasal, intraoral, nasopharyngeal, pharyngeal and / or tracheal irradiation. Fibre optics suitable for use in the invention are generally known in the art and commercially available, for example from CeramOptec GmbH, Bonn, Germany.

[0041] In certain preferred embodiments of the invention, a combined irradiation treatment is performed wherein irradiation of the nostril mucosa is carried out, preferably in both nostrils, using intra-nasal irradiation (i.e. irradiation is carried out inside the animal’s body) and, Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys simultaneously or, preferably, sequentially, the mucosa of the mouth and / or throat is irradiated from outside of the animal’s body.

[0042] In preferred embodiments of the invention treatment further comprises the step of applying the at least one photosensitizer on one or more parts of the milking equipment. Preferably, the one or more parts of the milking equipment comprise(s) at least any part(s) of the milking equipment coming into contact with the udder and / or teats during the milking process, preferably the teat cups, more preferably the inner parts of the teat cups. In a preferred embodiment, the photosensitizer is applied to all parts of a milking cluster.

[0043] When the photosensitizer is applied on one or more parts of the milking equipment as outlined above, it is preferred that the treatment further comprises a step of irradiating the one or more parts of the milking equipment, specifically those parts where the at least one photosensitizer has been applied to, with light comprising or having a wavelength causing the photosensitizer to be transferred to an active state.

[0044] Further details with respect to the above-described step of applying at least one photosensitizer on one or more parts of the milking equipment and, preferably, irradiating the one or more parts of the milking equipment with light comprising or having a wavelength causing the photosensitizer to be transferred to an active state, it is referred to the detailed description of the method of the invention for controlling infectious agents on one or more parts of a milking equipment as further described and disclosed herein below.

[0045] The light source used for irradiation according to the invention, which, according to the invention, may refer to light emitting element of a corresponding device or the device perse, is preferably a device comprising a light emitting diode (LED). In some embodiments of the invention, the LED device is a handheld light emitting device, more preferably a handheld LED device such as a device having the form and comprising the typical parts of, respectively, a torch or flashlight, respectively. In embodiments of the invention the light source emits coherent light, in which case the light source is a laser device emitting light of a specific wavelength. The laser device can be an LED laser device, and in certain embodiments, it may be a handheld laser LED device, as outlined above. In other preferred embodiments, the light source or light emitting device, respectively, can be a light source or device, respectively, emitting non-coherent light, preferably an LED device, more preferably a handheld LED device. Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys

[0046] It is a surprising finding according to the invention that it is sufficient for attaining substantial and strong virus inhibition to use a broadband light source, more preferably a broadband LED device, more preferably a broadband handheld LED device, preferably emitting white light, most preferred warm white light. In preferred embodiments of broadband LED devices, the LED light source is doted with Cer which shifts the potential dominant blue part (shorter wavelength) of the emitted light to longer wavelengths. In other preferred embodiments the LED devices can be one emitting non-coherent monochromatic light, preferably having a wavelength as further described below.

[0047] In certain preferred embodiments of the invention, where the animal’s respiratory tract is additionally treated a combined irradiation inside and / or from outside of the animal’s body can be attained using the same light source, but with different additional elements for irradiation inside the animal’s body and / or for irradiation outside of the animal’s body. In one preferred exemplary embodiment of this type, a handheld light emitting device, preferably an LED device, more preferred a handheld broadband LED device, most preferred a torch-type broadband LED device, can be equipped for inside irradiation, preferably intra-nasal irradiation, with a removably affixable light-guiding element. Preferably, a light-guiding element has a portion for removable fixation of the element to the, preferably handheld, LED device in the region, preferably an end of the LED device, where the emitted light exits the light emitting device, in case of a torch-type device an upper or (from the perspective of the user holding the torch-type device at the proximal part thereof) distal end thereof, such as a part or member forming a circumferential ring or partly circumferential part sized to fit the diameter of the light-emitting, preferably top or distal, part of the LED device, and a portion, i.e. a light guiding portion, having a conical shape extending from the fixation part, preferably having the form of the top conus of an intra-nasal pump spray device, such that the light guiding portion can be introduced into the animal’s body, preferably into a nostril of the animal. For irradiation from outside the animal’s body, the light emitting device can be equipped with a removably affixable element for positioning the device at a desired location of the animal’s body where the irradiation from outside the animal’s body is to take place. Preferably, a positioning element comprises a fixation portion, more preferred a fixation portion as described for the inside irradiation element, and an attachment portion for, preferably gently, attaching the light-emitting device to the desired portion of the animal’s body. In a preferred embodiment, the attachment portion comprises or consists of, respectively, a part sized to be positioned against a part of the animal’s body such as the upper lip in the case of irradiating the mouth and / or throat of the animal to be treated. In another preferred embodiment, the attachment portion comprises or consists of, respectively, a part or member sized to be positioned against a part of the animals nose such that at least Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys one, more preferably, both nostrils can be irradiated from the outside of the animal’s body. In preferred embodiments, the (preferably removably) affixable elements are devised for single or multiple use such as made of a disposable material for single or multiple use. In other embodiments, the removably affixable elements may be sterilized after one or more such as tow to five, for example two, three or four uses. In preferred embodiments of the invention, a light emitting device, preferably a handheld device, more preferably a broadband LED device and removably affixable elements for inside and / or outside irradiation, preferably elements as described above, can be included in a kit, preferably together with a container comprising the photosensitizer, preferably a solution thereof, such as, in highly preferred embodiments, a nasal spray device, preferably adapted to the size of the nose and / or nostril(s) of the animal to be treated.

[0048] For irradiating the at least part of the udder, preferably the teats, it is preferred in certain embodiments of the invention, that the light emitting device, preferably an LED device, more preferably a broadband LED device, particularly preferred broadband white LED, is integrated into a teat cup device or is a part thereof such as integrated into or being a part of, respectively, the photosensitizer application cluster device as described above. The general design of a teat cup device is known in the art and further outlined above with respect to the application of the photosensitizer. The light emitting device integrated is preferentially an LED device which is designed such that the emitted light reaches at least part of the treat which part includes the tip of the treat, more preferably essentially the complete teat. The light emitting devie, preferably the LED device, can preferably arranged on or, more preferably, integrated into the inner wall of the teat cup, preferably an arrangement of individual small LEDs or a light-guiding element having multiple portions where the light exists the light guiding portions of the light guiding element, wherein the multiple LEDs or the light-guiding element surrounds, preferably concentric, the at least part of the teat, preferably substantially the complete teat.

[0049] In the context of teat cup devices for use in the invention, it is preferred that both, application devices for application of the at least one photosensitizer, preferably a spraying or nebulizing device such as a dip sprayer or dip nebulizer, and light emitting devices such as LED devices as outlined above, are integrated into, attached to or being part of, respectively, a teat cup. For teat cup devices comprising more than one teat cup, the preferred embodiments outlined above for the photosensitizer application devices such as a spraying or nebulizing device, also apply to the light emitting devices integrated into or connected to or being part of one or more teat cup(s). Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys

[0050] Devices according to the invention for applying the photosensitizer and / or for irradiating the area(s) of the animal as described herein may also be integrated in or connected or be a part of, respectively, milking parlors. Miking parlors comprising devices according to the invention for applying the photosensitizer and / or for irradiating the relevant area(s) of the animal as described herein are also an aspect of the invention.

[0051] In one embodiment, a milking parlor of the invention comprises the typical components of a milking parlor and may have a parallel design, a tandem design, a herringbone design or a rotary design. In one embodiment, the parlor comprises one or more of the above-described teat cup devices per milking stall, wherein the teat cup device is designed for applying the at least one photosensitizer or solution thereof to the udder, preferably the teats. The teat cup device preferably comprises a number of teat cups being equal to the number of teats of the animal to be processed for milking, each teat cup having a connection such as a tubing line or duct, to a container comprising the photosensitizer or a solution thereof as further described below wherein the container is designed to be pressurized such that a desired amount of photosensitizer or solution thereof is applied to the teats via the teat cup(s).

[0052] In further preferred embodiments, preferably of the type described in the preceding paragraph, the milking parlor comprises teat cup devices as described herein for irradiating the at least part of the udder, at least one or more teats, as outlined herein. In one embodiment, the parlor comprises one or more of the above-described teat cup irradiation devices per milking stall, wherein the teat cup irradiation device is designed for irradiating at least a part of the udder, preferably the teats.

[0053] In further preferred embodiments, the parlor comprises teat cup devices as outlined herein above wherein the teat cup device is designed to provide both, photosensitizer application and irradiation functionality.

[0054] Preferred photosensitizers for use in the invention are photoactivatable phenothiazine derivatives, more preferably photoactivatable phenothiazine dyes. Phenothiazine photosensitizers for use in the invention typically have a structure according to the following general formula (I): Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys with D and D' each being an electron donor group, and wherein the positions C-1 , C-2, C-4, C-6, C-8 and / or C-9 of the phenothiazine ring system may be substituted by a substituent preferably selected from substituted or unsubstituted lower alkyl, preferably Ci-3-al kyl , particularly preferred methyl, or lower alkenyl, preferably C2-3-alkenyl, amino, halo, and cyano. Preferably, D and D’ are each independently a NRR’ group with R and R’ being preferably independently selected from H, substituted or unsubstituted lower alkyl, preferably Ci-3-alkyl, particularly preferred methyl, and lower alkenyl, preferably C2-3-alkenyl.

[0055] Particularly preferred phenothiazine derivatives for use in the invention are methylene blue, new methylene blue, toluidine blue and mixtures thereof.

[0056] The photosensitizer for use in the invention, preferably a phenothiazine derivative as described above, is typically applied in form of a composition containing at least one photosensitizer such as a photoactivatable phenothiazine in combination with at least one excipient and / or diluent, preferably at least one pharmaceutically acceptable excipient and / or diluent. Preferred diluents / excipients for use in the invention are typically water, preferably sterilized water, more preferably sterilized distilled water, or aqueous solutions such saline or buffered saline solutions such as PBS, whereby it is understood that such diluents and / or excipients are preferably sterilized. In preferred embodiments of the invention, the at least one photosensitizer such as as a photoactivatable phenothiazine derivative, is present in an aqueous solution, preferably a hypotonic aqueous solution of about 0 to about 0.7 % (w / v) salt, preferably NaCI.

[0057] It has been surprisingly found according to the invention that photosensitizers as taught herein, preferably phenothiazine derivatives of above formula (I), particularly preferred methylene blue, new methylene blue, toluidine blue or mixtures thereof, can be applied in comparatively very low concentrations for effectively combating viruses causing respiratory conditions. In preferred embodiments the composition comprises a photosensitizer for use in the invention, particularly preferred a phenothiazine derivative as defined herein, in a concentration of from about 0.00001 % (w / v) to about 0.1 % (w / v), preferably from about 0,0001 % (w / v) to about 0,001 % (w / v).

[0058] The photosensitizer, preferably contained in a composition as outlined above, is preferably administered to at least a part of the other, preferably the teat(s), and, in certain embodiments, also to the respiratory tract of the animal through nasal and / or oral application. For example, the photosensitizer, particularly the composition containing at least one Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys photosensitizer (i.e. one or more of such photosensitizers) as outlined above may be administered via a pipette or similar device. For administration to deeper parts of the respiratory tract tube systems known in the art equipped with a syringe reservoir at its proximal part can be used. In preferred embodiments, allowing for reaching the upper and lower parts of the respiratory tract of the animal to be treated, the photosensitizer(s) is (are) preferably administered by use a device configured to administer the photosensitizer(s), preferably a composition containing the photosensitizer(s), in spray or nebulized form. Typically, such a device comprises a nebulizer element and a container comprising a composition containing one or more photosensitizers as described above. Devices for applying the photosensitizer, preferably a photosensitizer composition as taught herein, to one or more teats have been elaborated above.

[0059] The invention is also directed to such medical devices for administration of the photosensitizers in spray or nebulized, respectively, form. In particular, the present invention provides a pharmaceutical device comprising a nebulizer and a container containing at least one photosensitizer, optionally in combination with at least one pharmaceutically acceptable excipient and / or diluent, wherein preferred embodiments have been already described in detail herein-above.

[0060] As already noted above, the wavelength or wavelength spectrum of the light emitted by the light source depends on the particular photosensitizer. Preferred phenothiazine photosensitizers for use in the invention typically absorb light in the visible to near infra-red light of the electromagnetic wave spectrum. For example, in the visible spectrum, methylene blue absorbs light in the wavelength region of from about 530 nm to about 700 nm, new methylene absorbs light in the wavelength region of from about 500 nm to about 700 nm, and toluidine blue absorbs light in the region of from about 520 nm to about 700 nm. In preferred embodiments, the photosensitizer is typically activated by irradiation with light have a wavelength of wavelengths, respectively, in the range of from about 500 nm to about 820 nm. As already indicated above, the light source or light emitting device, respectively, for use in the invention emits light typically within this wavelength region, whereby the light source can emit light in broadband region, preferably, of the above indicated visible to near infrared spectrum, preferably of about 500 nm to about 820 nm. Particularly preferred, the wavelength used for activating the photosensitizer, preferably one or more of the abovedescribed phenothiazines, preferably, methylene blue and / or new methylene blue and / or toluidine blue, most preferred methylene blue, is at or around 590 nm such as from about 550 nm to about 630 nm, preferably about 570 to about 610 nm, more preferably about 585 nm to about 595 nm, most preferred 589 nm or 590 nm. Preferably, such light is emitted by Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys an LED device, preferably LED devices as described in the various preferred embodiments as outlined herein, which, in certain preferred embodiments of the invention can emit noncoherent light.

[0061] In other preferred embodiments of the invention, the invention makes use of the light absorption of phenothiazine photosensitizers as outlined herein in the near infrared region. In certain embodiments of this type, the photosensitizer-activating light is in the near infrared region of the electromagnetic spectrum, preferably from about 780 nm to about 820 nm, more preferably around or at 810 nm such as from about 800 nm to about 820 nm, most preferred 810 nm. Near infrared light has the advantage that it is absorbed to a lesser extent by body components so that it can reach into deeper into the irradiated regions as defined above. The fact of the wavelength dependency of light scattering which is higher for longer wavelengths further contributes to this effect, and at wavelengths of at or around 810 nm the scattering coefficient is higher than the absorption coefficient, and furthermore the scattering is a forward scattering further contributing to the higher depth of penetration. Such light preferably has a depth of penetration of about 5 to 10 cm which makes it particularly suitable for the optional irradiation from the outside of the animal’s body such as for irradiating the at least part of the udder of the animal wherein the at least part of the udder includes one or more, preferably all, teats, and optionally, for irradiating the respiratory tract from the outside of the animal’s body.

[0062] In the context of irradiation in the near infrared region of the electromagnetic spectrum, preferably from about 780 nm to about 820 nm, more preferably around or at 810 nm such as from about 800 nm to about 820 nm, most preferred about 810 nm, the present invention also provides a photodynamic treatment, particularly for treatment of viral infections of the respiratory tract, more preferably for treatment and / or prevention of the viral infections as described above, by application of a photosensitizer such as a phenothiazine photosensitizer according to the definition as outlined above, more preferably selected from methylene blue, new methylene blue and toluidine blue, to a desired region, especially at least a part of the udderof the animal, the at least part of the udder including one or more, preferably, all, teats, and, optionally, to a region of the respiratory tract (such as those as described above) of the animal to be treated, and transcutaneous irradiation of said region. In some embodiments of this aspect of the invention, the region of treatment also includes application of the photosensitizer and transcutaneous irradiation to one or both, preferably both, maxillary sinuses, and / or one or both, preferably both, paranasal sinuses, and / or one or both, preferably both, frontal sinuses. Besides the viral infections as outlined herein-above, such Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys treatment will be also applicable to any infections, such as bacterial and / or viral and / or fungal, infections of the sinuses, preferably the above-mentioned sinuses.

[0063] Depending on the particular photosensitizer, it may be desired for efficient energy transfer to select a wavelength or wavelength region, respectively, at or at least near the absorption maximum of the photosensitizer. “Near the absorption maximum” in the context of the invention typically means a range around the absorption maximum of from about - 50 nm to about + 50 nm, preferably from about -20 nm to about + 20 nm, more preferably from about - 10 nm to about + 10 nm of the absorption maximum. The absorption characteristics, including an absorption maximum of the photosensitizer, preferably of a phenothiazine derivative as described herein, is typically in the visible to near infrared range of the light spectrum, will depend on the biological setting, i.e. in which the photosensitizer is present as well as whether the animal is irradiated from outside of the body or within the body, and will also depend on and thus can be tuned by the components of a composition in which the photosensitizer(s) is present for application.

[0064] In other embodiments of the invention, the wavelength used for activating the photosensitizer is selected from regions of the, typically visible, absorption spectrum being more remote from an absorption maximum of the respective photosensitizer. In this context of the invention, the term “remote from an absorption maximum” of a photosensitizer for use in the invention refers to a wavelength.

[0065] The duration and number of times of irradiation of the at least part of the udder of the animal wherein the at least part of the udder includes one or more, preferably all, teats, and optionally, at least part of the respiratory tract of the animal to be treated according to the invention varies according the specific photosensitizer, the wavelength or wavelength region of the light and on whether irradiation of the respiratory tract (or part(s) thereof) is carried from the outside or inside of the body of the animal to be treated. Typically, the irradiation is carried out, for example when irradiation is carried out from the outside of the animal’s body, one or more times, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 times or more in one or more sessions at a day of treatment. The treatment can be repeated for two or more days, wherein the days of treatment can be uninterrupted or interrupted by one or more days where no treatment takes place. Preferably, the duration of the irradiation per irradiation incidence (i.e. one or more times as outlined above) is about 1 to about 50000 s, preferably from about 30 s to about 90 s, more preferably from about 45 s to about 75 s, most preferably about 60 s. Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys

[0066] In preferred embodiments of the invention the at least part of the udder of the animal wherein the at least part of the udder includes one or more, preferably all, teats, and, optionally, the at least part of the respiratory tract is irradiated, e.g. when irradiation is carried out from outside of the animal, with an energy density of 50 to 150 J / cm2, preferably 80 to 120 J / cm,’ more preferably 90 to 110 J / cm, most preferably 100 J / cm2. Preferred emitted light intensities, especially in the case of irradiation with non-coherent light, preferably by LED devices such as broadband LED devices or LED devices emitting light at about or around about 590 nm (as outlined above), range from about 5000 Lux to about 100000 Lux, preferably from about 10000 Lux to about 30000 Lux, most preferred from about 20000 Lux. Especially preferred devices for irradiating the at least part of the udder of the animal wherein the at least part of the udder includes one or more, preferably all, teats, have already been elaborated above.

[0067] In general, the treatment of the invention is directed against the viral infections in dairy cattle, most preferred bovine cattle, caused by an enveloped or non-enveloped virus, preferably an influenza virus.

[0068] Preferably, the virus is an influenza A virus.

[0069] In preferred embodiments, the influenza virus is an avian influenza virus., more preferably selected from influenza subtypes H5, H7 and H9 influenza virus, most preferred an influenza virus selected from the subtypes H5N1, H7N9, H5N6 and H9N2.

[0070] The present invention is also directed to a method for prevention and / or treatment of a viral infection in dairy cattle, most preferably bovine cattle, preferably viruses as outlined above comprising the steps of (i) administering at least one photosensitizer to at least a part of the udder of the animal wherein the at least part of the udder includes one or more, preferably all, teats; and (ii) irradiating said at least part of the udder of the animal wherein the at least part of the udder includes one or more, preferably all, teats at least part of the respiratory tract of the animal with light having a wavelength causing the photosensitizer to be transferred into an activated state. In certain embodiments of the invention the method for the prevention and / or treatment of viral infection in dairy cattle, most preferably, bovine cattle, also includes the administration of the at least one photosensitizer to at least a part of the respiratory tract of the animal, preferably intra-nasal and / or intra-oral and / or pharyngeal administration of the at least one photosensitizer, and irradiating said at least part of the respiratory tract from the inside and / or outside of the animal whereby it is understood that the administration to the at least part of the respiratory tract can be carried out simultaneously in step (i) as described above, and the irradiation of the at least part of the respiratory tract can Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys be carried out simultaneously with the irradiation step (ii) as described above. In other embodiments of the invention, the administration of the photosensitizer to at least a part of the respiratory tract can be carried out as a step (iii) of the method, and the step of irradiating said at least part of the respiratory trance can be carried our as a step (iv) of the method.

[0071] The present invention is also directed to a process for milking dairy cattle involving the above treatment method.

[0072] In particular, a process for milking dairy cattle animal comprises the steps of:

[0073] (I) carrying out the method for prevention and / or treatment of a viral infection in dairy cattle as defined herein;

[0074] (II) attaching the teat cups of the milking equipment to the teats of the animal; and

[0075] (III) milking the animal using the milking equipment.

[0076] Preferably, the method comprises the further step (IV) of carrying out the inventive method for prevention and / or treatment of a viral infection in dairy cattle, i.e. the milking method preferably comprises the repeating of step (I) after the milking step (III).

[0077] Preferred embodiments of photosensitizers and compositions containing same, administration regimens, light sources and light emitting devices, wavelengths, duration and times of irradiation for use in the inventive treatment method have already described herein above.

[0078] While washing and disinfecting treatments of the udder, at least the teats, are widely practiced (with the latter being preferably carried out using the photosensiziert / irradation treatment against viruses according to the invention), it has been recognized according to the present invention that a source of the spreading of infectious agents in dairy cattle is the transmission of infectious agents through untreated or at least insufficiently treated milking equipment, especially the teat cups, particularly the inner parts thereof, after a milking process and their repeated application to individual animals.

[0079] The present invention is therefore further directed to a method of controlling infectious agents on one or more parts of a milking equipment comprising the step of applying at least one photosensitizer on said one or more parts of the milking equipment. The one or more parts of the milking equipment preferably comprise(s) at least any part(s) of the milking equipment coming into contact with the udder and / or teats during the milking process, preferably the Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys teat cups, more preferably the inner parts of the teat cups. In preferred embodiments of the invention, the at least one photosensitizer is applied to all parts of a milking cluster..

[0080] According to the intention, the expression ..controlling infectious agents" is meant to refer the controlling of one or more infectious agents. The term “controlling" according to the invention preferably means that the one or more parts of the milking equipment as outlined herein has a reduced number of infectious agents than before the treatment and / or, in other embodiments, a reduced number of infectious agents in comparison to untreated corresponding one more more parts of milking equipment. In preferred embodiments, the number of infectious agents is reduced at least by 50 %, more preferably, by at least 60 %, still more preferred by at least 70 %, even more preferred by at least 80 %, yet more preferred by at least 90 %, yet even more preferred by at least 95 % such as by at least 96 %, by at least 87 %, by at least 98 % or event at least 99 %, in comparison to the respective untreated one or more parts of the milking equipment and / or the respective one or more parts of the milking equipment before the inventive treatment. The term “controlling infectious agents", in the context of the invention, is also understood in certain embodiments to mean that the method is a preventive method, i.e. the method is embodied as method for at least limiting, preferably preventing, the colonization or re-colonization of one or more parts of mining equipment by infectious agents (one or more infectious agents).

[0081] The present method for controlling infectious agents on milking equipment is also embodied herein as a method for limiting, preferably preventing, the spreading of infectious agents in dairy cattle by milking equipment contaminated with infectious agents (one or more infectious agents). Under a further aspect, the method of controlling infectious agents on milking equipment according to the invention is also embodied herein as a method for disinfecting and / or for decontaminating one or more parts of milking equipment for dairy cattle from infectious agents.

[0082] In particular with respect to controlling bacteria in the context of the invention it is one beneficial aspect of the method according to the present invention that the photosensitizer as used herein is capable of substantially harming, preferably destroying, the extracellular matrix (ECM) of bacteria. The ECM of bacteria is an complex intricate and diverse structure of proteins, polysaccharides and extracellular DNA (eDNA) which bacteria use for, inter alia, attaching to organisms, making up biofilms as well as for sensing of chemical signals. Common techniques of disinfecting treatments are incapable of or at least not sufficiently capable of attacking bacterial ECM so that the photosensitizer treatment of one or more parts Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys of milking equipment according to the invention is superior over conventional anti-bacterial treatments at least in this regard.

[0083] The term “infectious agent(s)“ generally relates to any fungus, microbe, bacterium, virus, viroid that may be present on one or more parts of the milking equipment. Preferred infectious agents are infectious agents being capable of infecting and / or persisting in or on or at least colonizing (including re-colonizing) in or on dairy cattle, most preferred bovine dairy cattle.

[0084] Preferred infectious agents to be controlled are bacteria and viruses. Preferred viruses have already been outlined above in the context of photosensitizer treatment of dairy cattle against viruses (or in the context of the inventive use of photosensitizer against viral infections in dairy cattle). Thus, viral infectious agents to be controlled by the present method are in general, enveloped or non-enveloped viruses, preferably influenza virus. Preferably, the virus is an influenza A virus. In preferred embodiments, the influenza virus is an avian influenza virus., more preferably selected from influenza subtypes H5, H7 and H9 influenza virus, most preferred an influenza virus selected from the subtypes H5N1, H7N9, H5N6 and H9N2.

[0085] Preferred bacteria include, but are not limited to, gram-positive or gram-negative bacteria more preferred bacteria (gram-positive or gram-negative) causing mastitis in dairy cattle, most preferred causing bovine mastitis.

[0086] Non-limiting examples of mastitis-causing, in particular bovine mastitis-causing, bacteria are disclosed or reviewed, respectively, in the prior art, for example, in Cheng and Han (2020), Asian-Australasian Journal of Animal Sciences 33 (11), 1699-1713, with particular reference given to Section „BOVINE MASTITIS RISK FACTORS", Subsection ..Pathogen Factor", and the pathogens mentioned in that sections are incorporated herein by reference.

[0087] Thus, mastitis-causing bacteria, preferably bovine mastitis causing bacteria, more preferably bacteria causing intra-mammary infection (I M I), include, but are not limited to, contagious and non-contagious (environmental) bacteria, with contagious bacteria, i.e. bacteria which are typically transmitted from cow to cow, in particular during the milking process, being particularly preferred. Non-limiting example of contagious bacteria include contagious Staphylococcus ssp. such as preferably S. aureus, contagious Streptococcus ssp. such as preferably S. agalactiae, contagious Mycoplasma ssp. such as preferably M. bovis, and contagious Corynebacterium. Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys

[0088] Non-limiting examples of environmental bacteria which may cause mastitis, preferably bovine mastitis, typically include Escherichia col\, Enterococcus ssp. such as preferably E. faecalis and E. faecium, coagulase-negative Staphylococcus ssp. such as preferably S. simulates, S, chromogens, S. hyicus and S. epidermis, and non-contagious Streptococcus ssp. such as preferably S. uberis.

[0089] It is to be understood that the method for controlling infectious agents on one or more parts of a milking equipment may directed to specifically controlling each of the infectious agents, in particular bacteria and viruses, as well as including any combination thereof.

[0090] Preferably, the method for controlling infectious agents on one or more parts of a milking equipment according to the invention comprises the further step of irradiating the one or more parts of the milking equipment with light comprising or having a wavelength causing the photosensitizer to be transferred to an active state.

[0091] Preferred irradiation for the method of controlling infectious agents according to the invention can be carried out by an LED device, preferably a laser LED device, or a non-coherent light emitting LED device, preferably a broadband LED device. In preferred embodiments of the invention, the irradiating device is a handheld LED device, preferably one of the aforementioned types. In other preferred embodiments of the method of controlling infectious agents according to the invention the light emitting device is a stationary or a mobile nonhandheld device preferably a stationary or mobile non-handheld LED device such as a stationary or mobile non-handheld laser LED device, or a stationary or non-handheld mobile non-coherent light emitting LED device, preferably a stationary or mobile non-handheld broadband LED device.

[0092] The method for controlling infectious agents according to the invention may be carried out in appropriately dimensioned, preferably closable, more preferably air and / or light tight closable, containers or closable, preferably air and / or light tight closable chambers, respectively, which are preferably equipped with means for applying the at least one photosensitizer to the one or more parts of a milking equipment and, more preferably with means for irradiating the one or more parts of a milking equipment, specifically the one or more parts of the milking equipment on which the at least one photosensitizer has been applied to. The container or chamber preferably comprises means for appropriately arranging the one or parts of the milking equipment to be treated in such a manner that the at least one photosensitizer can be applied to the one or more parts of the milking equipment and, preferably, such that the one or more parts of the milking equipment can be irradiated, Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys specially where the at least one photosensitizer has been applied to said one or more parts of the milking equipment. Preferred parts of milking equipments to be arranged in a container or chamber as disclosed herein (also referred to a ..treatment container" or „treatment chamber", respectively) are as outlined above, most preferably a milking cluster. Treatment containers or chamber, respectively, are also part of the present invention and can be dimensioned and designed, respectively, for arranging and treating (i.e. application of photosensitizer and, preferably irradiation) multiple milking equipment parts such as multiple mining cluster such as 2, 3, 4, 5, 6, 7, 8, 9, 10 or more milking clusters therein.

[0093] Preferably, the at least one photosensitizer is applied to the one or more parts of the milking by a spraying or nebulizing device. The nebulizing or spraying device(s) is / are preferably integrated into or is / or part of treatment containers or treatment chambers as outlined above.

[0094] The method for controlling infectious agents on milking equipment is preferably carried out before milking of dairy cattle, preferably before attaching the teat cups of the milking equipment, preferably being part of a milking cluster, to the udder and / or teats, respectively, preferably directly before the milking process. In preferred embodiments, the method for controlling infectious agents after teat stimulation. Preferably, the method for controlling infectious agents is carried out directly before the the teat cups of a milking equipment are attached to dairy cattle.

[0095] Preferred embodiments of irradiation times, wavelengths, light intensities, light energies, photosensitizes and photosensitizer solutions or suspensions have already been outlined above and are also preferred embodiments of the method for controlling infections agents of the invention.

[0096] Preferably, the method for controlling infectious agents on milking equipment according to the invention is adapted for milking equipment of dairy cattle as already outlined above, most preferred bovine dairy cattle.

[0097] The present invention also relates to a further method for milking dairy cattle using the method for controlling infectious agents on one or more parts of a milking equipment as disclosed herein.

[0098] In particular, the further method for milking dairy cattle comprises the steps of:

[0099] (a) carrying out the method the method of controlling infectious agents on one or more parts of a milking equipment; Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys

[0100] (b) attaching the teat cups of the milking equipment to the teats of the animal; and

[0101] (c) milking the animal using the milking equipment.

[0102] Preferably, the method comprises the further step (d) of carrying out the inventive method for controlling infectious agents on one or more parts of a milking equipment, i.e. the milking method preferably comprises the repeating of step (a) after the milking step (c).

[0103] Further milking processes of the invention combine the use of the photosensitizer antiviral treatments as described and disclosed herein and the method for controlling infectious agents on one or more parts of milking equipment as described and disclosed herein.

[0104] Further preferred details and embodiments of the invention, in particular treatment conditions as well as devices, photosensitizers, light sources etc. have been described herein-before and will further be exemplified in the following non-limiting examples.

[0105] EXAMPLES

[0106] Example 1 : PDT treatment of bovine cattle against avian flu infection

[0107] Photosensitizer solution: 0.001 % (v / v) methylene blue aqueous solution.

[0108] Photosensitizer applicator: dip sprayer comprising the photosensitizer solution.

[0109] Light source: handheld broadband LED device or handheld LED device emitting light at 589 nm at 20000 Lux.

[0110] Uninfected cows and cows having a confirmed influenza (H5N1) infection are treated directly before milking. The photosensitizer solution is applied by use of the photosensitizer applicator per cow to each teat such that each teat is covered with the photosensitizer solution. Thereafter, each teat is irradiated from all directions for 60 seconds for one to three times.

[0111] The procedure is repeated at every milking event for one week.

[0112] H5N1 Infection is monitored by H5N1 PCR directly before the first treatment and at days 1 to 7 after the first treatment on material taken from the animals by teat swab. Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys

[0113] Example 2: Method for controlling infectious agents on milking equipment

[0114] Photosensitizer solution: 0.001 % (v / v) methylene blue aqueous solution.

[0115] Photosensitizer applicator: conventional spraying device comprising the photosensitizer solution.

[0116] Light source: handheld broadband LED device or handheld LED device emitting light at 589 nm at 20000 Lux.

[0117] After a milking process of uninfected cows and cows having a confirmed bacterial mastitis infection and / or confirmed influenza (H5N1) infection, the used respective milk clusters are either left untreated or treated with the photosensitizer solution using the spraying device and thereafter either left under daylight for 10 min or irradiated completely from all sides either using the broadband LED device or using the LED device emitting 589 nm at 2000 Lux, each irradiation lasting for 60 s to 3 min for one to three times. Non-used milking clusters are treated in parallel as negative controls.

[0118] Infestation with infectious agents on the milking clusters is monitored by taking test swabs from the inside of each teat cup, the outside of each teat cup and the outside of each tubing of the respective milk cluster before and, where applied, after treatment as outlined above. The test swabs are subjected to analysis of presence and number of bacteria and by H5N1 PCR for presence of H5N1 viruses.

Claims

Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark AttorneysClaims1. A photosensitizer for use in the treatment of viral infections in dairy cattle wherein the photosensitizer is at least applied to at least a part of the udder of the animal wherein the at least part of the udder includes one or more, preferably all, teats.

2. The photosensitizer for use of claim 1 wherein the treatment comprises irradiating at least a part of the udder of the animal wherein the at least part of the udder includes one or more, preferably all, teats with light comprising or having a wavelength causing the photosensitizer to be transferred to an active state.

3. The photosensitizer for use of claim 1 wherein the photosensitizer is additionally applied to the respiratory tract of the animal, preferably intra-nasally and / or intra-orally and / or pharyngeally.

4. The photosensitizer for use of claim 3 wherein the treatment additionally comprises irradiating the respiratory tract of the animal from outside of the animal with light comprising or having a wavelength causing the photosensitizer to be transferred to an active state.

5. The photosensitizer for use according to any one of claims 2 to 4 wherein the light is emitted by a light emitting diode (LED) device.

6. The photosensitizer for use of claim 5 wherein the LED device is a laser LED device, or a non-coherent light emitting LED device, preferably a broadband LED device.

7. The photosensitizer for use of claim 6 or 7 wherein the LED device is a handheld LED device.

8. The photosensitizer for use of claim 6 wherein the LED device is integrated in or is connected to or forms a part of a teat cup device.

9. The photosensitizer for use of claim 2 to 8 wherein the at least part of the udder and, optionally, respiratory tract, is / are irradiated one or more times for a period of fromHabermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys about 1 to about 50000 s, preferably from about 30 s to about 90 s, more preferably from about 45 s to about 75 s, most preferably about 60 s.

10. The photosensitizer for use of claim 9 wherein the at least part of the udder and, optionally, respiratory tract, is irradiated with an energy density of 50 to 150 J / cm2, preferably 80 to 120 J / cm2,’ more preferably 90 to 110 J / cm2, most preferably 100 J / cm2.11 . The photosensitizer for use of claim 9 wherein the at least part of the udder and, optionally, the respiratory tract, is / are irradiated with a light intensity at from about 5000 Lux to about 100000 Lux, preferably from about 10000 Lux to about 30000 Lux, most preferred from about 20000 Lux.

12. The photosensitizer for use according to any one of the preceding claims wherein the photosensitizer is a photoactivatable phenothiazine derivative, preferably a photoactivatable phenothiazine dye, more preferably a phenothiazine derivative having a structure of the following formula (I)whereinD and D' each are an electron donor group, and wherein the positions C-1 , C-2, C-4, C-6, C-8 and / or C-9 of the phenothiazine ring system may be substituted by a substituent preferably selected from substituted or unsubstituted lower alkyl, preferably Ci-3-alkyl, particularly preferred methyl, or lower alkenyl, preferably C2-3- alkenyl, amino, halo, and cyano, preferably, D and D’ are each independently a NRR’ group with R and R’ being preferably independently selected from H, substituted or unsubstituted lower alkyl, preferably Ci-3-alkyl, particularly preferred methyl, and lower alkenyl, preferably C2-3-alkenyl.

13. The photosensitizer for use of claim 12 wherein the phenothiazine dye is selected from the group consisting of methylene blue, new methylene blue, toluidine blue and mixtures thereof.Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys14. The photosensitizer for use of claim 12 or 13 wherein the photoactivatable phenothiazine derivative is applied as a composition containing from 0.0001 (v / v) to 1.0000 % (v / v), preferably from 0.0001 % (v / v) to 0.005 % (v / v), more preferably from about 0.0005 to about 0.002 % (v / v), most preferably about 0.001 % (v / v) of said photoactivatable phenothiazine derivative.

15. The photosensitizer for use of claim 14 wherein the phenothiazine derivative is present in an aqueous solution, preferably a hypotonic aqueous solution of about 0 to about 0.7 % (w / v) salt, preferably NaCI.

16. The photosensitizer for use according to any one of claim 12 to 15 wherein the treatment comprises irradiating the at least part of the udder and, optionally, respiratory tract respiratory tract, of the animal with light comprising or having a wavelength selected from 500 nm to 820 nm of the electromagnetic spectrum.

17. The photosensitizer for use of claim 16 wherein the light has a wavelength in the range of from 550 nm to 630 nm, preferably 570 to 610 nm, more preferably 585 nm to 595 nm, most preferred the light has a wavelength of 589 nm.

18. The photosensitizer for use of claim 16 wherein the light has a wavelength in the range of from 780 nm to 820 nm, preferably from about 800 nm to about 820 nm, most preferred the light has a wavelength of 810 nm.

19. The photosensitizer for use according to any one of the preceding claims wherein the photosensitizer is applied to the at least part of the udder, said part of the udder including one or more teats, preferably all teats, and, optionally, the respiratory tract, by a spraying or nebulizing device.

20. The photosensitizer for use of claim 19 wherein the spraying or nebulizing device is integrated in or is connected to or forms a part of a teat cup device.

21. The photosensitizer for use according to any one of the preceding claims wherein the viral infection is caused by an enveloped or non-enveloped virus.

22. The photosensitizer for use of claim 21 wherein the virus is an influenza virus.Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys23. The photosensitizer for use of claim 22 wherein the influenza virus is an influenza A virus.

24. The photosensitizer according to any one of claims 21 to 23 wherein the influenza virus is an avian influenza virus.

25. The photosensitizer for use according to any one of claims 21 to 24 wherein the influenza virus is selected from the group consisting of influenza subtypes H5, H7 and H9 influenza virus.

26. The photosensitizer for use of claim 25 wherein the influenza virus is selected from the group consisting of the subtypes H5N1, H7N9, H5N6 and H9N2.

27. The photosensitizer for use according to any one of the preceding claims wherein the dairy cattle is selected from the group consisting of bovine cattle, sheep, goat, horse, water buffalo and camelids.

28. The photosensitizer for use according to any one of the preceding claims wherein the treatment is a pre-milking treatment.

29. The photosensitizer for use of claim 28 wherein the pre-milking treatment is carried out after teat stimulation.

30. The photosensitizer for use of according to any one of the preceding claims wherein the treatment further comprises the step of applying the at least one photosensitizer on one or more parts of the milking equipment.

31. The photosensitizer for use of claim 30 wherein the one or more parts of the milking equipment comprises at least any part(s) of the milking equipment coming into contact with the udder and / or teats during the milking process, preferably the teat cups, more preferably the inner parts of the teat cups.

32. The photosensitizer for use of claim 30 or 31 wherein the photosensitizer is applied to all parts of a milking cluster.

33. The photosensitizer for use according to any one of claims 30 to 32 further comprising the step of irradiating the one or more parts of the milking equipment withHabermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys light comprising or having a wavelength causing the photosensitizer to be transferred to an active state.

34. A method of controlling infectious agents on one or more parts of a milking equipment comprising the step of applying at least one photosensitizer on said one or more parts of the milking equipment.

35. The method of claim 34 wherein the one or more parts of the milking equipment comprise(s) at least any part(s) of the milking equipment coming into contact with the udder and / or teats during the milking process, preferably the teat cups, more preferably the inner parts of the teat cups.

36. The method of claim 34 or 35 wherein the photosensitizer is applied to all parts of a milking cluster.

37. The method according to any one of claims 34 to 36 comprising the further step of irradiating the one or more parts of the milking equipment with light comprising or having a wavelength causing the photosensitizer to be transferred to an active state.

38. The method of claim 37 wherein the light is emitted by a light emitting diode (LED) device.

39. The method of claim 38 wherein the LED device is a laser LED device, or a noncoherent light emitting LED device, preferably a broadband LED device.

40. The method of claim 38 or 39 wherein the LED device is selected from the group consisting of a handheld LED device, a non-handheld mobile LED device and a stationary LED device.41 . The method according to any one of claims 37 to 40 wherein the one or more parts of the milking equipment is / are irradiated one or more times for a period of from about 1 to about 50000 s, preferably from about 30 s to about 90 s, more preferably from about 45 s to about 75 s, most preferably about 60 s.

42. The method of claim 41 wherein the one or more parts of the milking equipment is / are irradiated with an energy density of 50 to 150 J / cm2, preferably 80 to 120 J / cm2,’ more preferably 90 to 110 J / cm2, most preferably 100 J / cm2.Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys43. The method of claim 41 wherein the one or more parts of the milking equipment is / are irradiated with a light intensity at from about 5000 Lux to about 100000 Lux, preferably from about 10000 Lux to about 30000 Lux, most preferred from about 20000 Lux.

44. The method according to any one of claims 34 to 43 wherein the photosensitizer is a photoactivatable phenothiazine derivative, preferably a photoactivatable phenothiazine dye, more preferably a phenothiazine derivative having a structure of the following formula (I)whereinD and D' each are an electron donor group, and wherein the positions C-1 , C-2, C-4, C-6, C-8 and / or C-9 of the phenothiazine ring system may be substituted by a substituent preferably selected from substituted or unsubstituted lower alkyl, preferably Ci-3-alkyl, particularly preferred methyl, or lower alkenyl, preferably C2-3- alkenyl, amino, halo, and cyano, preferably, D and D’ are each independently a NRR’ group with R and R’ being preferably independently selected from H, substituted or unsubstituted lower alkyl, preferably Ci-3-alkyl, particularly preferred methyl, and lower alkenyl, preferably C2-3-alkenyl.

45. The method of claim 44 wherein the phenothiazine dye is selected from the group consisting of methylene blue, new methylene blue, toluidine blue and mixtures thereof.

46. The method of claim 44 or 45 wherein the photoactivatable phenothiazine derivative is applied as a composition containing from 0.0001 (v / v) to 1.0000 % (v / v), preferably from 0.0001 % (v / v) to 0.005 % (v / v), more preferably from about 0.0005 to about 0.002 % (v / v), most preferably about 0.001 % (v / v) of said photoactivatable phenothiazine derivative.Habermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys47 The method of claim 46 wherein the phenothiazine derivative is present in an aqueous solution, preferably a hypotonic aqueous solution of about 0 to about 0.7 % (w / v) salt, preferably NaCI.

48. The method according to any one of claims 44 to 47 wherein the method comprises irradiating the one or more parts of the milking equipment is irradiated with light comprising or having a wavelength selected from 500 nm to 820 nm of the electromagnetic spectrum.

49. The method of claim 48 wherein the light has a wavelength in the range of from 550 nm to 630 nm, preferably 570 to 610 nm, more preferably 585 nm to 595 nm, most preferred the light has a wavelength of 589 nm.

50. The method of claim 48 wherein the light has a wavelength in the range of from 780 nm to 820 nm, preferably from about 800 nm to about 820 nm, most preferred the light has a wavelength of 810 nm.

51. The method according to any one of claims 34 to 50 wherein the photosensitizer is applied to the one or more parts of the milking by a spraying or nebulizing device.

52. The method according to any one of claims 34 to 51 wherein the method is carried out before milking of dairy cattle.

53. The method of claims 52 wherein the method is carried after teat stimulation.

54. The method of claim 52 or 53 wherein the method is carried out directly before the teat cups of a milking equipment are attached to dairy cattle.

55. A process for milking dairy cattle animal comprising the steps of:(a) carrying out the method according to any one of claims 34 to 51 on one or more parts of a milking equipment;(b) attaching the teat cups of the milking equipment to the teats of the animal; and(c) milking the animal using the milking equipment.

56. The process of claim 55 comprising, after step (c), the further step ofHabermann, Hruschka & Schnabel Patentanwalte • European Patent and Trade Mark Attorneys(d) carrying out the method according to any one of claims 34 to 51 on the one or more parts of the milking equipment.

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