Ex Parte Bell et alDownload PDFPatent Trial and Appeal BoardMar 15, 201712674727 (P.T.A.B. Mar. 15, 2017) Copy Citation United States Patent and Trademark Office UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O.Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 12/674,727 04/18/2011 Gordon Bell 71657-US-REG-ORG-P 8898 85981 7590 03/15/2017 Syngenta Corp Protection, Inc. 410 Swing Road Greensboro, NC 27409 EXAMINER HIRT, ERIN E ART UNIT PAPER NUMBER 1616 MAIL DATE DELIVERY MODE 03/15/2017 PAPER Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte GORDON BELL, CLAIR LOUISE HARRIS, and IAN DAVID TOVEY Appeal 2016-002243 Application 12/674,727 Technology Center 1600 Before MELANIE L. McCOLLUM, JEFFREY N. FREDMAN, and TIMOTHY G. MAJORS, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal1 under 35 U.S.C. § 134 involving a composition the form of an emulsion concentrate. The Examiner rejected the claims obvious. We have jurisdiction under 35 U.S.C. § 6(b). Statement of the Case Background Nowadays, the Formulation Chemist is required to address a number of environmental criteria when developing new formulations. Ideally, a suitable solvent will display many or all of the following properties: an excellent dissolving power for pesticides or other biologically active compounds; made from plant or animal renewable resources; low skin irritation; 1 Appellants identify the Real Party in Interest as the Syngenta Crop Protection, LLC (see App. Br. 3). Appeal 2016-002243 Application 12/674,727 an ability to reduce the skin irritation associated with aggressive formulation components, such as sodium lauryl sulphate; low ecotoxicity, for example to daphnia; low volatile organic content; and a high flash point. The compositions of the present invention comprise a solvent which displays all or many of these attractive properties. (Spec. 1:16-24). The Claims Claims 1, 2, 4—18, and 20-23 are on appeal. Claim 1 is representative and reads as follows: 1. A composition in the form of an Emulsion Concentrate (EC) comprising a compound of formula I CH3CH(0H)C(=0)NR1R2 (I) where R1 and R2 are each CEE; and at least one biologically active compound, which comprises at least one aromatic five and/or six membered ring wherein the ring contains at least one nitrogen as a ring member, with the proviso that the biologically active compound is not cyproconazole. The Issues A. The Examiner rejected claims 1, 2, 4—18, and 20-23 under 35 U.S.C. § 103(a) as obvious over Zima,2 Sehring,3 Razzak,4 Ohsumi,5 and EPA6 (Final Act. 4—9). 2 Zima et al., DE 1 083 501, published June 15, 1960. We rely upon a translation of Zima, added to the record herewith, with pages numbered 1—6 (“Zima Transl.”). 2 Appeal 2016-002243 Application 12/674,727 B. The Examiner provisionally rejected claims 1 and 2 on the ground of nonstatutory provisional obviousness-type double patenting as being unpatentable over claim 1 of copending US application 12/674,741 (Final Act. 2-3). A. 35 U.S.C. § 103(a) over Zima, Sehring, Razzak, Ohsumi, and EPA The Examiner finds “Zima teaches a compound of formula I wherein applicant's R1 and R2 are methyl. Zima also teaches wherein these lactamide compounds are useful for solubilizing poorly water soluble, and water insoluble drugs and agricultural chemicals (specifically fungicides, insecticides, herbicides)” (Final Act. 5). The Examiner finds the “active can comprise a 5 or 6 membered aromatic ring comprising nitrogen” (Id.). The Examiner acknowledges that “Zima does not specifically teach wherein the composition comprises additional solvents selected from those listed in instant claim 5 or is used to form emulsion concentrates or contain adjuvants such as emulsifiers” but finds “Sehring teaches lactamides of formula I as solubilizers for poorly soluble agrochemical actives, specifically triforine and Saprol” (Id.). 3 Sehring, R., DE 41 30 189 Al, published Mar. 18, 1993. We rely upon a translation of Sehring, added to the record herewith, with pages numbered 1-12 (“Sehring Transl.”). 4 Razzak et al., US 2003/0180350 Al, published Sept. 25, 2003 (“Razzak”). 5 Ohsumi et al., US 4,837,242, issued June 6, 1989 (“Ohsumi”). 6 EPA Pesticide Fact Sheet, Isopyrazam, http://www.epa.gov/ pesticides/chem_search/reg^actions/pending/fs_PC-129222_05- Oct-ll.pdf (Oct. 5 2011) (“EPA”). 3 Appeal 2016-002243 Application 12/674,727 The Examiner finds “Razzak teaches microemulsion pesticidal compositions comprising poorly water soluble avermectins” and lactamides “are useful as solubilizing agents for these lipophilic/hydrophobic pesticides” (Final Act. 6). The Examiner finds “EPA fact sheet teaches that isopyrazam is a poorly water soluble fungicide” and Ohsumi teaches “pyrazole fungicides, a class of fungicides which would include isopyrazam, are often formulated with organic solvents” (Id.). The Examiner finds it obvious to “try dimethyl lactamide as taught by Zima to solubilize isopyrazam, because these compounds were well known in the art to be useful for solubilizing poorly water soluble/water insoluble actives, and isopyrazam is known in the art to be a very poorly soluble agrochemical active” (Final Act. 7). The issue with respect to these rejections is: Does the evidence of record support the Examiner’s conclusion that the prior art renders the claims obvious? Findings of Fact 1. The Specification teaches a composition comprising a compound of formula I CH3CH(0H)C(=0)NR! R2 (I) where R1 and R2 are each independently hydrogen; or Ci-6 alkyl, C2-6 alkenyl or C3-6 cycloalkyl, each of which is optionally substituted by up to three substituents independently selected from phenyl, hydroxy, C1-5 alkoxy, morpholinyl and NR3R4 where R3 and R4 are each independently C1-3 alkyl; or phenyl optionally substituted by up to three substituents independently selected from C1-3 alkyl; or R1 and R2 together with the nitrogen atom to which they are attached form a morpholinyl, pyrrolidinyl, piperidinyl or azepanyl ring, each of which is 4 Appeal 2016-002243 Application 12/674,727 optionally substituted by up to three substituents independently selected from C1-3 alkyl. (Spec. 1:32 to 2:10). 2. Zima teaches using monosubstituted or disubstituted a-oxyacid amides of the formula (Ri = alkyl or phenyl, R2 and R3 mean methyl or ethyl, it also being possible for R2 to be hydrogen), in particular lactic acid diethyl amide as solubilizers for producing aqueous solutions of medications poorly soluble or insoluble in water. (Zima Transl. 2). 3. Zima teaches the “main area of application of the invention is for medications. However, it can often be advantageous to put plant growth promoters, insecticides, fungicides, and other pesticides into an aqueous solution by the use of the solubilizers according to the invention” (Zima Transl. 2). 4. Zima teaches “[s]olubilizers ... are used for producing aqueous solutions of poorly soluble or insoluble active substances” (Zima Transl. 2). Zima also teaches the “particular advantage of the new solubilizers consists in their very low toxicity ... A further advantage consists in the fact that the named oxyacid amides are very stable and produce neutrally reacting aqueous solutions” (Zima Transl. 2—3). 5 Appeal 2016-002243 Application 12/674,727 5. Zima teaches an example where “25 ccm of a 12% solution of lactic acid diethyl amide dissolve 1.25 g of l-benzyl-3-ethyl-6,7-dimethoxy- isoquinolinehydrochloride under weak heating” (Zima Transl. 3). 6. Sehring teaches compounds with the general formula R-CO-NH-CH2-CH2OH, in which R = methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl (CH3-CHOH or HO-CH2CH2-) which appear in nearly all commercial plant protection agents that are used in the form of emulsion concentrates, can be used as extremely favorable solvents. This substance class replaces the sometimes hazardous and toxic aliphatic and aromatic hydrocarbons still used in enormous amounts and which are not safe for humans, animals and the environment. (Sehring Transl. 3). Sehring teaches “formulation of saprol (fungicide) with lactic acid ethanolamide can be mentioned as an example of the superiority of the emulsion concentrate” (Sehring Transl. 4). 7. Razzak teaches components that “are present in such proportions such that they form microemulsions” (Razzak 124) where “the lipophilic active is selected from the group including macrocyclic lactones, including avermectins and milbemycins” (Razzak 119) and the “the organic solvent is selected from the group including . . . N-(B-hydroxyethyl) lactamide . . . and other pharmaceutically acceptable excipients” (Razzak 121). 8. Razzak teaches “[a]fter devising a base formulation we conducted further experiments to determine what other factors affect the uptake of water into the compositions” (Razzak 134) including “varying amounts of sesame oil, ethyl oleate and medium chain mono- and di glycerides while maintaining the ratio of the surfactant and solvent, in this 6 Appeal 2016-002243 Application 12/674,727 case polysorbate 80 and benzyl alcohol in a ratio of 2:15 and 7:15 respectively” (Razzak 140). 9. Ohsumi teaches fungicides that include five membered rings with nitrogen (see Ohsumi 1:20—50) that may be “formulated into emulsifiable concentrates” with organic solvents (see Ohsumi 8:46—64) and that “can be used as an active ingredient of fungicides to be used for paddy field, plowland, orchard, pasture, turf and the like” (Ohsumi 9:25—27). 10. The Examiner finds the “EPA fact sheet teaches that isopyrazam is a poorly water soluble fungicide, which is highly soluble in a variety of organic solvents including aromatic solvents” (Ans. 6). Principles of Law “The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSRInt’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). Analysis We adopt the Examiner’s findings of fact and reasoning regarding the scope and content of the prior art (Final Act. 4—9; FF 1—10) and agree that the claims are rendered obvious by Zima, Sehring, Razzak, Ohsumi, and EPA. Because we rely upon translations of Zima and Sehring that were not previously of record (see, e.g., Ans. 7)7, we will designate our affirmance of this rejection as a New Grounds of Rejection. We address Appellants’ arguments below. 7 See MPEP § 706.02 II (“If the document is in a language other than English and the examiner seeks to rely on that document, a translation must be obtained so that the record is clear as to the precise facts the examiner is relying upon in support of the rejection.”) 7 Appeal 2016-002243 Application 12/674,727 Claim 1 Appellants contend “the teaching of Zima does not guide one skilled in the art to (1) choose dimethyl lactamide from the teaching of Zima” (App. Br. 13). We do not find this argument persuasive. We note that Appellants’ own disclosed genus is significantly larger than the genus disclosed by Zima (FF 1—2), subverting Appellants’ genus/species argument. More significantly, Petering addressed a prior art reference in an anticipation context that disclosed a small genus of chemical compounds, finding: A simple calculation will show that, excluding isomerism within certain of the R groups, the limited class we find in Karrer contains only 20 compounds. However, we wish to point out that it is not the mere number of compounds in this limited class which is significant here but, rather, the total circumstances involved, including such factors as the limited number of variations for R, only two alternatives for Y and Z, no alternatives for the other ring positions, and a large unchanging parent structural nucleus. With these circumstances in mind, it is our opinion that Karrer has described to those with ordinary skill in this art each of the various premutations here involved as fully as if he had drawn each structural formula or had written each name. In re Petering, 301 F.2d 676, 681—682 (CCPA 1962). Here, in an obviousness context, Zima’s structure contains only six alternatives based on selection of R2 and R3 being either methyl or ethyl or for R2 hydrogen, and with a very limited set of additional alternatives based on R1 being limited to alkyl or phenyl substituents (FF 2). Just as in Petering, the limited number of variations and the basic parental structure support the Examiner’s position 8 Appeal 2016-002243 Application 12/674,727 that the selection of dimethyl lactamide from this limited genus would have been obvious, if not anticipated, by Zima. We recognize that “lists and genera are often treated differently” but “[t]his distinction collapses when the class of compounds that falls within the genus is so limited that a person of ordinary skill in the art can “at once envisage each member of this limited class.’” In re Gleave, 560 F.3d 1331, 1337—1338 (Fed. Cir. 2009) citing Eli Lilly & Co. v. Zenith Goldline Pharms., Inc., 471 F.3d 1369, 1376 (Fed. Cir. 2006). Zima teaches such a limited genus that dimethyl lactamide may be immediately envisaged, and therefore would have been obvious to the person of ordinary skill in the art. Appellants contend that “the phrase ‘A composition in the form of an Emulsion Concentrate (EC)’ recited in independent claim 1 limits the structure of the claimed invention, and consequently should be given weight” (Reply Br. 3). Appellants further contend “the teaching of Zima does not guide one skilled in the art to subsequently (1) seek out the divergent teachings of (a) Sehring directed to an emulsion concentrate comprising (i) a solvent other than dimethyl lactamide, namely, solvents having Sehring’s formula” (App. Br. 14). We agree with Appellants that the claims require the formulation in an emulsion concentrate form. However, we are not persuaded that the prior art does not render the claimed emulsion concentrate obvious. Zima teaches an organic solvent useful in solubilizing active agents like insecticides, fungicides and pesticides (FF 3) and both Sehring and Ohsumi suggest dissolving such active agents into emulsion concentrates using organic solvents (FF 6, 9). Razzak also teaches dissolving active agents into 9 Appeal 2016-002243 Application 12/674,727 emulsions with organic solvents (FF 7). The ordinary artisan would have had reason to select Zima’s solvent not only as a known structural equivalent (cf. Final Act. 8) but because a “particular advantage of the new solubilizers consists in their very low toxicity ... A further advantage consists in the fact that the named oxyacid amides are very stable and produce neutrally reacting aqueous solutions” (FF 4). Appellants contend that: although the teaching of Zima mentions “fungicides, insecticides and pesticides” as possible components in Zima’s disclosed aqueous solutions, Zima does not suggest to one skilled in the art (1) to incorporate “poorly water soluble/water insoluble actives of any type,” into Zima’s disclosed aqueous solutions, or (2) that Zima’s disclosed solubilizers are suitable for use with “poorly water soluble/water insoluble actives of any type” (App. Br. 14). We are not persuaded. Zima teaches “[s]olubilizers ... are used for producing aqueous solutions of poorly soluble or insoluble active substances” (FF 4) and teaches “it can often be advantageous to put plant growth promoters, insecticides, fungicides, and other pesticides into an aqueous solution by the use of the solubilizers according to the invention” (FF 3). Thus, the ordinary artisan would have found it obvious to use Zima’s solubilizers for prior art known poorly soluble insecticides, fungicides, or pesticides in general, consistent with Wrigley, which found a “strong case of obviousness based on the prior art references of record. [The claim] recites a combination of elements that were all known in the prior art, and all that was required to obtain that combination was to substitute one 10 Appeal 2016-002243 Application 12/674,727 well-known . . . agent for another.” Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC, 683 F.3d 1356, 1364 (Fed. Cir. 2012). The same situation occurs here, where all that is required is to solubilize known insecticides, fungicides, or pesticides using Zima’s disclosed solubilizers (FF 2—10). Appellants contend: the teaching of Zima guides one skilled in the art to form aqueous solutions, not emulsion concentrates. It is difficult for Appellants to understand why one skilled in the art, given the teaching of Zima directed to aqueous solutions comprising a solubilizer having Zima’s formula and an active ingredient, would have been guided and/or motivated to seek out the teaching of Sehring, and subsequently choose to form an emulsion concentrate instead of an aqueous solution as guided within the teaching of Zima. (App. Br. 14). We do not find this argument persuasive because Sehring teaches emulsion concentrates are a known delivery form for fungicides (FF 6) and Razzak and Ohsumi teach emulsions formed with organic solvents for solubilizing specific active compounds (FF 7, 9). Thus, the prior art in combination suggests the use of both organic solvents and emulsions, including emulsion concentrates, while Sehring teaches “the superiority of the emulsion concentrate” (FF 6), a specific reason to select that delivery form. The reason need not be found in the prior art, but may be implicit when the improvement’ is technology-independent and the combination of references results in a product or process that is more desirable” as in the emulsion concentrate form suggested by Sehring in the instant case. See DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1368 (Fed. Cir. 2006). 11 Appeal 2016-002243 Application 12/674,727 Appellants contend because “Sehring clearly guides one skilled in the art, when forming an emulsion concentrate comprising a water-insoluble fungicide (i.e., triforine), to utilize a solubilizer having Sehring’s formula” that “the proposed combination of the teachings of Zima, Sehring, Razzak, Oh sum i and the EPA Fact Sheet (even if deemed a proper combination of teachings) actually teaches away from Appellants’ claimed composition” (App. Br. 15). We find the teaching away argument unpersuasive. A teaching away requires a reference to actually criticize, discredit, or otherwise discourage the claimed solution. See In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004) (“The prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed”). Appellants do not persuasively identify any teaching in any of the cited prior art that criticizes, discredits, or discourages the use of Zima’s solubilizers. Appellants contend “‘[o]ne cannot use hindsight reconstruction’” and therefore “the proposed combination of the teaching of Zima with the teaching of Sehring, the teaching of Razzak, the teaching of Ohsumi and the EPA Fact Sheet is improper” (App. Br. 15). We are not persuaded. While we are fully aware that hindsight bias may plague determinations of obviousness, Graham v. John Deere Co., 383 U.S. 1, 36 (1966), we are also mindful that the Supreme Court has clearly stated that the “combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable 12 Appeal 2016-002243 Application 12/674,727 results.” KSR, 550 U.S. at 416. In the instant case, selection of Zima’s solubilizer for use in emulsion concentrate delivery of fungicides, pesticides, or insecticides as taught by Sehring, using compounds taught by Razzak, and Ohsumi would have reasonably been expected to yield the predictable result of an effective fungicidal, pesticidal, or insecticidal composition (FF 2—10). Appellants contend that: Although the holding in the Takeda case involved motivation for modifying a known compound, Appellants respectfully submit that a similar analysis applies to the required motivation for (1) selecting and combining possible composition components from hundreds, thousands (or hundreds of thousands) of possible composition components, and (2) forming an emulsion concentrate with the selected composition components. (App. Br. 16—17). We are not persuaded. Takeda involves the situation where none of the species in the prior art genus fell within the scope of the claim, since “[p]ioglitazone differs from compound b in two respects, and one would have to both homologate the methyl group of compound b and move the resulting ethyl group to the 5-position on the pyridyl ring in order to obtain pioglitazone.” Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd, 492 F.3d 1350, 1360 (Fed. Cir. 2007). In the instant case, every compound of Zima falls within the broad scope of Appellants’ disclosure (FF 1), and the selection of R groups to satisfy claim 1 is limited by the very small genus size of known equivalents in Zima as already discussed. See Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989) (“That the ‘813 patent discloses a 13 Appeal 2016-002243 Application 12/674,727 multitude of effective combinations does not render any particular formulation less obvious.”) Claim 15 Appellants contend that the combination fails to teach or suggest an emulsion concentrate comprising, inter alia, (i) a compound of formula 1; (ii) an agrochemical; and (iii) a solvent, wherein the ratio of (i) compound of formula 1 to (ii) the agrochemical to (iii) the solvent is 1:1:1 or 2:1:1 or 2:1:2 or 3:1:1 or 3:1:2 or 4.5:1:4.5 or 6:1:3 as recited in dependent claim 15. (App. Br. 19). We are not persuaded because Razzak evidences that optimization of the ratio of components for active agent delivery in emulsions is routine (FF 8). Therefore, we agree with the Examiner that “it would have merely been the optimization of amounts of lactamide to isopyrazam/agrochemical active to carrier which were already taught in the prior art in order to develop the composition of the instant claims” (Ans. 7). See In re Aller, 220 F.2d 454, 456 (CCPA 1955) (“[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.”) Claims 16—18, and 23 Appellants contend the prior art “fails to teach or suggest an emulsion concentrate comprising, inter alia, (i) dimethyl lactamide and (ii) 3- difluoromethyl-1 -methyl-1 H-pyrazole-4-carboxylic acid(9-isopropyl- l,2,3,4-tetrahydro-l,4-methano-naphthalen-5-yl)-amide as recited in dependent claim 16” (App. Br. 20; cf. App. Br. 24). 14 Appeal 2016-002243 Application 12/674,727 We do not find this argument persuasive because, as discussed already, Zima suggests solvents in a limited genus including dimethyl lactamide (FF 2) for use with fungicides (FF 3) such as isopyrazam (the compound name for the (ii) that was suggested by EPA) (FF 10). Appellants provide no evidence of any secondary consideration for combining these known components. As will be discussed next, the prior art teaches treatment of plants with fungicidal emulsions (FF 6, 9). Claims 21 and 22 We recognize, but find unpersuasive, Appellants’ contention that the prior art fails to teach or suggest a method of controlling an agricultural pest comprising application to the pest, to a locus comprising it or to a surface on which it is capable of being present, of a pesticidally effective amount of a composition according to claim 1 as recited in dependent claim 21 (App. Br. 22). Sehring specifically teaches treatment of plants with fungicides (FF 6) as does Ohsumi (FF 9). The ordinary artisan, after forming an emulsion concentrate containing an insecticide, fungicide, or pesticide, would have reasonably found it obvious to apply this composition to surfaces hosting pests such as plants (FF 9). Conclusion of Law The evidence of record supports the Examiner’s conclusion that the prior art renders the claims obvious. 15 Appeal 2016-002243 Application 12/674,727 B. Obviousness-type double patenting We summarily affirm the obviousness-type double patenting rejection because Appellants do not address the rejection (see App. Br. 5, footnote 1). See Manual of Patent Examining Procedure § 1205.02 (“If a ground of rejection stated by the examiner is not addressed in the appellant’s brief, that ground of rejection will be summarily sustained by the Board.”) SUMMARY We affirm the obviousness and provisional obviousness double patenting rejections, but designate our affirmance of the obviousness rejection as a New Ground of Rejection because we relied upon translations not previously of record. This decision contains a new ground of rejection pursuant to 37 C.F.R. § 41.50(b). Section 41.50(b) provides “[a] new ground of rejection pursuant to this paragraph shall not be considered final for judicial review.” Section 41.50(b) also provides: When the Board enters such a non-final decision, the appellant, within two months from the date of the decision, must exercise one of the following two options with respect to the new ground of rejection to avoid termination of the appeal as to the rejected claims: (1) Reopen prosecution. Submit an appropriate amendment of the claims so rejected or new Evidence relating to the claims so rejected, or both, and have the matter reconsidered by the examiner, in which event the prosecution will be remanded to the examiner. The new ground of rejection is binding upon the examiner unless an amendment or new Evidence not previously of Record is made which, in the opinion of the examiner, overcomes the new ground of rejection designated in the decision. Should the examiner reject the 16 Appeal 2016-002243 Application 12/674,727 claims, appellant may again appeal to the Board pursuant to this subpart. (2) Request rehearing. Request that the proceeding be reheard under § 41.52 by the Board upon the same Record. The request for rehearing must address any new ground of rejection and state with particularity the points believed to have been misapprehended or overlooked in entering the new ground of rejection and also state all other grounds upon which rehearing is sought. Further guidance on responding to a new ground of rejection can be found in the Manual of Patent Examining Procedure § 1214.01. AFFIRMED: 37 C.F.R, § 41.500?) 17 Notice of References Cited Application/Control No. 12/674,727 Applicant(s)/Patent Under Reexamination Examiner Hirt Art Unit 1616 Page 1 of 1 U.S. PATENT DOCUMENTS * Document Number Country Code-Number-Kind Code Date MM-YYYY Name CPC Classification US Classification A us- B us- C US- D US- E US- F US- G US- H US- 1 US- J US- K US- L US- M US- FOREIGN PATENT DOCUMENTS * Document Number Country Code-Number-Kind Code Date MM-YYYY Country Name CPC Classification N O P Q R S T NON-PATENT DOCUMENTS * Include as applicable: Author, Title Date, Publisher, Edition or Volume, Pertinent Pages) U Translation of Zima et al., DE 1 083 501, published June 15, 1960. V Translation of Sehring, R., DE 41 30 189 Al, published Mar. 18, 1993 w X *A copy of this reference is not being furnished with this Office action. (See MPEP § 707.05(a).) Dates in MM-YYYY format are publication dates. Classifications may be US or foreign. U.S. Patent and Trademark Office PTO-892 (Rev. 01-2001) Notice of References Cited Part of Paper No. PTO 118567 CC=DE DATE=19930318 KIND=A1 PN=4130189 NEW EMULSION CONCENTRATES FOR USE IN PLANT PROTECTION [Neue Emulsionskonzentrate fur den Einsatz im Pflanzenschultz] UNITED STATES PATENT AND TRADEMARK OFFICE Washington, D.C. February 2017 Translated By: Phoenix Translations 100 N. Avenue B Elgin, TX 78621 PUBLICATION COUNTRY DOCUMENT NUMBER DOCUMENT KIND PUBLICATION DATE PUBLICATION DATE APPLICATION NUMBER APPLICATION DATE INTERNATIONAL CLASSIFICATION5 IDENTIFICATION SYMBOL SEQUENCE NOS. FOR OFFICE USE DOMESTIC CLASSIFICATION PRIORITY COUNTRY PRIORITY NUMBER PRIORITY DATE UNIVERSAL DECIMAL CODE LIST OF PRIOR ART DOCUMENTS ADDITION TO INVENTOR APPLICANT DE 4130189 A1 (19) : (11) : (12) : (13) : (43) : 19930318 (45) : (21) : P4130189.7 (22) : 19910911 (51) : A 01 N 25/02 A 01 N 37/26 // A0IN 25/30 (52) : (33) : (31) : (32) : (53) : (56) : (61) : P4112873.7 (72) : Inventor will be mentioned later (71) : Dr. Richard H. Sehring 1 TITLE FOREIGN TITLE (54) : New Emulsion Concentrates for Use in Plant Protection (54A) : Neue Emulsionskonzentrate fur den Einsatz im Pflanzenschultz 2 /I Description It was found that compounds with the general formula R-CO-NH-CH2-CH2OH, in which R = methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl (CH3- CHOH or HO-CH2CH2-)which appear in nearly all commercial plant protection agents that are used in the form of emulsion concentrates, can be used as extremely favorable solvents. This substance class replaces the sometimes hazardous and toxic aliphatic and aromatic hydrocarbons still used in enormous amounts and which are not safe for humans, animals and the environment. All the substances are very plant-compatible and in conjunction with emulsifiers promote penetration of the active ingredients into the plants and therefore produce a certain systemic effect and therefore an improvement of effect. All compounds of this type are readily biodegradable and produce no residues in the plants or in soil. The compounds are easily prepared from the methyl ester of the formula R-CO-OCH3 with ethanolamine at elevated temperature. 3 The formulation of saprol (fungicide) with lactic acid ethanolamide can be mentioned as an example of the superiority of the emulsion concentrate. The preparation of an emulsion concentration of saprol with aliphatic or aromatic hydrocarbons has not been possible because of the poor solubility. An emulsion concentrate can only be obtained with the toxicologically critical dimethylformamide. It has now been shown that when toxicologically safe lactic acid ethanolamide is used, a very stable and highly effective emulsion concentrate is obtained with simultaneous addition of surfactants, like polyoxyethylene fatty acid esters, polyoxyethylene aliphatic alcohol ethers, alkyl sulfonates and aryl sulfonates. Claims 1. Use of ethanolamides of the general formula R-CO-NH-CH2-CH2OH R = methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl (CH3-CHOH or HO-CH2CH2-) as solvents for production of emulsion concentrates that are used for general plant protection. 2. Lactic acid ethanolamide in combination with triforine and a surfactant, like polyoxyethylene fatty acid esters, polyoxyethylene aliphatic alcohol ethers, alkyl sulfonates and aryl sulfonates. 3. Fungicides, insecticides or herbicides consisting of 10-40% of a given active ingredient, 50-80% of an ethanolamide of the above 4 formula (claim 1) as well as 3-20% of a surfactant according to example 2. 5 PUBLICATION COUNTRY (19) : DE DOCUMENT NUMBER (11) : 1083501 DOCUMENT KIND (12) : A (13) : PUBLICATION DATE (43) : 19600615 PUBLICATION DATE (45) : APPLICATION NUMBER (21) : APPLICATION DATE (22) : 19590326 INTERNATIONAL CLASSIFICATION (51) : A 61 k IDENTIFICATION SYMBOL DOMESTIC CLASSIFICATION (52) : 30 h 2/30 PRIORITY COUNTRY (33) : PRIORITY NUMBER (31) : PRIORITY DATE (32) : UNIVERSAL DECIMAL CODE (53) : LIST OF PRIOR ART DOCUMENTS (56) : INVENTOR (72) : Dr . Otto Zima et al. APPLICANT (71) : E. Merck AG, Darmstadt TITLE (54) : Method for Production of Solutions of Drugs Poorly Soluble or Insoluble in Water 6 FOREIGN TITLE (54A) : Verfahren zur Herstellung von Losungen in Wasser schwer- oder unloslicher Arzneimittel 7 /I A number of solubilizers that have a significant (sometimes desired, but in many cases also interfering) physiological effect in the employed amounts are used to produce aqueous solutions of active ingredients, especially drugs that are poorly soluble or insoluble. On the other hand, there is a lack of agents for this purpose that have no effect in the employed amounts. The present invention consists of using mono- or disubstituted a-hydroxy acid amides of the formula \, (Ri = alkyl or phenyl, R2 = alkyl or phenyl, R2 and R3 denote methyl or ethyl, in which R2 can also be hydrogen), especially lactic acid diethylamide as a solubilizer to produce aqueous solutions of drugs that are poorly soluble or insoluble in water. The mentioned compounds are miscible with water in any ratio. Individually or mixed with each other in aqueous solution, they have an excellent solution capacity for active ingredients of any type that are poorly soluble or insoluble in water. The main area of application of the invention lies in drugs, but plant growth agents, insecticides, fungicides and other pesticides can often be advantageously brought into aqueous solution by using the solubilizers according to the invention. The special advantage of the new solubilizers is their very low toxicity so that the harmful or even interfering side effects that cannot be ruled out during use of many known solubilizers are avoided. The substances according to the invention do not have an intrinsic pharmacological effect; thus, 1 g of substance per kilogram of body weight injected intravenously in mice is tolerated without symptoms. Another advantage is that the mentioned hydroxy acid amides are readily storable and produce neutral reacting aqueous solutions. The pH value of the solution generally lies between 6 and 7. Examples 1. 150 mg A1-dehydrocortisone is dissolved under heating in 25 cm3 of a 30% aqueous lactic acid diethylamide solution containing 10% alcohol. No crystals precipitate from the sterilized solution on cooling. 2. 100 mg A1-dehydrocortisone is dissolved under heating in 10 cm3 of a 50% solution of lactic acid diethylamide. / 2 3. 25 cm3 of a 12% solution of lactic acid diethylamide dissolves under weak heating 1.25 g l-benzyl-3-ethyl-6,7-dimethoxyisoquinoline hydrochloride. 4. 2.5 g l-benzyl-3-ethyl-6,7-dimethoxyisoquinoline and 1 g nicotinic acid are dissolved in 50 cm3 of an aqueous solution of lactic acid diethylamide. 9 5. 10 cm3 of a 30% solution of lactic acid diethylamide dissolves 100 mg of strophanthin under slight heating. 6. 4 g glycolic acid diethylamide in 10 cm3 water easily dissolves 200 mg theophylline. 7. 3 g glycolic acid diethylamide, 50 mg A1-dehydrocortisone and 1 cm3 alcohol in 10 cm3 of water produce a stable clear solution. 8. 6 g mandelic acid ethyl amide in 25 cm3 water produces a storable solution with 6 g dimethylaminophenyldimethylpyrazolone. 9. 100 mg theophylline is smoothly dissolved in a solution of 1 g mandelic acid ethyl amide in 10 cm3 water. 10. 10 g ajmalicine ethanesulfonate, 150 g lactic acid diethylamide, 100 cm3 alcohol and 50 cm3 IN acetic acid produce a clear storable solution made up to 1000 cm3 with water. 11. 5 g ethylcyclohexenylbarbituric acid is dissolved in 25 g lactic acid diethylamide and 10 g alcohol and made up to 100 cm3 with water. 12. 0.5 g phenylethylbarbituric acid produces a storable solution with 2.5 g lactic acid diethylamide, 1 g alcohol and 6 cm3 water. Comparative examples were produced with the a-hydroxy acid amides / 3 10 according to the invention and some known readily effective and chemically comparable solubilizers are shown in the following table. Dimethylaminophenyldimethylpyrazolone, theophylline and / 4 A1-dehydrocortisone were used as poorly soluble drugs. Ethylurethane, ethylenediamine, triethanolamine and methylacetamide were used as comparable solubilizers. Ethyl urethane Ethylene diamine Triethan olamine Methyl acetamide Solubilizer according to the invention Example Dimethylaminophenyldimethylpyrazolone . . 6 g 800 mg 1.4 g 3 . 9 g 6 g 8 Theophylline ...................................................................... 190 mg 2 0 0 mg 2 0 0 mg 15 0 mg 2 0 0 mg 6 A1-Dehydrocortisone ................................................... 14 0 mg 145 mg 15 0 mg 60 mg 15 0 mg 1 A1-Dehydrocortisone ................................................... 95 mg 100 mg 90 mg 2 8 mg 100 mg 2 / 3 The table shows how many grams or milligrams of the drug mentioned on the left can be brought into aqueous solution under otherwise identical conditions, using the known solubilizers listed above and the solubilizers according to the invention. From the figures in the table it is apparent that the a-hydroxy acid amides according to the invention generally have a better, or at least the same, solubilizing capacity as the known solubilizers. The solubilizers according to the present invention do not have an intrinsic pharmacological effect; their use is therefore also advantageous if their solubilizing effect is only just as high as the aforementioned known solubilizers, which have an intrinsic (in many cases undesired) pharmacological effect. 11 / 4 CLAIMS: 1. Method for production of solutions of drugs poorly soluble or insoluble in water, characterized by the fact that a-hydroxy acid amides of the formula , id Rt...CKOH....CO....K (Ri = alkyl or phenyl, R2 = alkyl or phenyl, R2 and R3 denote methyl or ethyl, in which R2 can also be hydrogen) are used as solubilizer. 2. Method according to claim 1, characterized by the use of lactic acid diethylamide as solubilizer. 12 PTO 118495 CC=DE DATE=19600615 KIND=B PN=1083501 METHOD FOR PRODUCING SOLUTIONS OF MEDICATIONS POORLY SOLUBLE OR INSOLUBLE IN WATER [VERFAHREN ZUR HERSTELLUNG VON LOSUNGEN IN WASSER SCHWER- ODER UNLOSLICHER ARZNEIMITTEL] Otto Zima, et al. UNITED STATES PATENT AND TRADEMARK OFFICE Washington, D.C. February 2017 Translated by: FLS, Inc. PUBLICATION COUNTRY DOCUMENT NUMBER DOCUMENT KIND PUBLICATION DATE IN BULLETIN INTERNATIONAL CLASSIFICATION APPLICATION NUMBER APPLICATION DATE PRIORITY NUMBER PRIORITY DATE PRIORITY COUNTRY APPLICANT INVENTORS TITLE (19 (11 (12 (46 (51 (21 (22 (31 (32 (33 (71 (72 (54 DE 1083501 B 19600615 A61K 47/18 DEI 95 9M04 0 970 19590326 DEI 95 9M04 0 970 19590326 DE E. MERCK AG ZIMA, OTTO; SCHORRE, GUSTAV METHOD FOR PRODUCING SOLUTIONS OF MEDICATIONS POORLY SOLUBLE OR INSOLUBLE IN WATER FOREIGN TITLE [54A] : VERFAHREN ZUR HERSTELLUNG VON LOSUNGEN IN WASSER SCHWER- ODER UNLOSLICHER ARZNEIMITTEL 1 Description /I Solubilizers that produce a distinct - often desirable, but in many cases disturbing - physiological effect, are used for producing aqueous solutions of poorly soluble or insoluble active substances, in particular medications. However, there is a lack of agents that are practically without effect, i.e. in the amounts used, for this purpose. The present invention consists in using monosubstituted or disubstituted a-oxyacid amides of the formula Jt iq — 0 H 0 H—G 0 “ N' 'll, (Ri = alkyl or phenyl, R2 and R3 mean methyl or ethyl, it also being possible for R2 to be hydrogen), in particular lactic acid diethyl amide as solubilizers for producing aqueous solutions of medications poorly soluble or insoluble in water. The named compounds are miscible with water in any ratio. They possess an outstanding dissolving capacity for substances of any kind that are poorly soluble or insoluble in water, individually or in a mixture. The main area of application of the invention is for medications. However, it can often be advantageous to put plant growth promoters, insecticides, fungicides, and other pesticides into an aqueous solution by the use of the solubilizers according to the invention. The particular advantage of the new solubilizers consists in their very low toxicity, with which the harmful or quite disturbing * Numbers in the margin indicate pagination in the foreign text. 2 side-effects that cannot be eliminated in case of using many known solubilizers, are avoided. The substances according to the invention do not possess any pharmacological effect; thus in the case of mice e.g. 1 g of substance per kilogram of body weight, injected intravenously, is tolerated without symptoms. A further advantage consists in the fact that the named oxyacid amides are very stable and produce neutrally reacting aqueous solutions. The pH value of the solutions for the most part is between 6 and 7. Examples 1. 150 mg of Zh-dehydrocortisone are dissolved under heating in 25 ccm of a 30% aqueous lactic acid diethyl amide solution, which contains 10% alcohol. No crystals precipitate from the sterilized solution upon cooling. 2. 100 mg of Zh-dehydrocortisone are dissolved under heating in 10 ccm of a 50% solution of lactic acid diethyl amide. 3. 25 ccm of a 12% solution of lactic acid diethyl amide dissolve 1.25 g of l-benzyl-3-ethyl-6,7-dimethoxy-isoquinoline- hydrochloride under weak heating. 4. 2.5 g of l-benzyl-3-ethyl-6,7-dimethoxy-isoquinoline and 1 g of nicotinic acid are dissolved in 50 ccm of an aqueous solution of lactic acid diethyl amide. 5. 10 ccm of a 30% solution of lactic acid dimethyl amide dissolve 100 mg of strophantine under slight heating. 3 6. 4 g of glycolic acid diethyl amide in 10 ccm of water smoothly dissolve 200 mg of theophylline. 7. 3 g of glycolic acid diethyl amide, 50 mg of h1- dehydrocortisone and 1 ccm of alcohol in 10 ccm of water give a constant clear solution. 8. 6 g of mandelic acid ethyl amide in 25 ccm of water with 6 g of dimethyl aminophenyl dimethyl pyrazolone gives a stable solution. 9. 100 g of theophylline dissolve smoothly in a solution of 1 g of mandelic acid ethyl amide in 10 ccm of water. 10. 10 g of ajmalicine ethane sulfonate, 150 g of lactic acid diethyl amide, 100 ccm of alcohol, and 50 ccm 1-n acetic acid, filled with water to 1000 ccm, give a clear stable solution. 11. 5 g of ethyl-cyclohexenyl-barbituric acid are dissolved in 25 g of lactic acid diethyl amide and 10 g of alcohol and filled with water to 100 ccm. 12. 0.5 g of phenyl-ethyl-berbituric acid with 2.5 g of lactic acid diethyl amide, 1 g of alcohol, and 6 ccm of water give a stable solution. The following table presents comparison experiments, which were conducted with the a-oxyacid amides according to the invention and Some known, very effective, and chemically more or less comparable [2_ solubilizers. Dimethyl aminophenyl dimethyl pyrazolones, theophylline, and h1- dehydrocortisone were used as the poorly soluble medications. Ethyl 4 urethane, ethylene diamine, triethanol amine, and methyl acetamide were used as comparable solubilizers. Ethyl- urethane Ethyl ene diamine Trietha nol amine Methyl acetam ide Solubili zer according to the invention Example Dimethyl aminophenyl dimethyl Pyrazolone....................................... 6 g 800 mg 1.4g 3.9 g 6g 8 Theophylline............................................. 190 mg 200 mg 200 mg 150 mg 200 mg 6 ZT-dehydrocortisone.......................... 140 mg 145 mg 150 mg 60 mg 150 mg 1 ZT-dehydrocortisone.......................... 95 mg 100 mg 90 mg 2 8 mg 100 mg 2 The table shows how many grams or milligrams one of the known medications indicated on the left can be put into an aqueous solution under the most equal possible other conditions with the use of the known solubilizers presented above as well as the solubilizers according to the invention. The numbers in the table show that the a- oxyacid amides according to the invention for the most part have a solubilizing effect that is better than, or at least the same as, the known solubilizers. The solubilizers according to the present invention do have no particular pharmacological effect; therefore their use is also advantageous when their solubilizing effect is only as great as that of the above-mentioned known solubilizers, which have a particular - in many case undesirable - pharmacological effect. 5 PATENT CLAIMS 1. A method for producing solutions of medications poorly soluble or insoluble in water, wherein a-oxyacid amides of the formula sv--choh--co..~n; XR, (Ri = alkyl or phenyl, R2 and R3 mean methyl or ethyl, it also being possible for R2 to be hydrogen) are used as solubilizers. 2. The method according to Claim 1, characterized by the use of lactic acid diethyl amide as solubilizer. 6 Copy with citationCopy as parenthetical citation