George Lahm et al.

Patent Trials and Appeals Board

Sep 2, 2021

2021001892 (P.T.A.B. Sep. 2, 2021)

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. 12/663,848 12/10/2009 George Philip Lahm 137738.00301 BA9399USPCT 8025 141914 7590 09/02/2021 AH PATENT DEPARTMENT BOEHRINGER INGELHEIM ANIMAL HEALTH USA INC. 3239 SATELLITE BLVD. BLDG. 500 DULUTH, GA 30096 EXAMINER COUGHLIN, MATTHEW P ART UNIT PAPER NUMBER 1626 NOTIFICATION DATE DELIVERY MODE 09/02/2021 ELECTRONIC 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. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): docket.ip@boehringer-ingelheim.com tiki.cantrell@boehringer-ingelheim.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte GEORGE PHILIP LAHM, JEFFREY KEITH LONG, and MING XU ____________ Appeal 2021-001892 Application 12/663,848 Technology Center 1600 ____________ Before DONALD E. ADAMS, CHRISTOPHER G. PAULRAJ, and DAVID COTTA, Administrative Patent Judges. ADAMS, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from Examiner’s decision to reject claims 27-31 (Appeal Br. 3). We have jurisdiction under 35 U.S.C. § 6(b). Oral argument was heard on August 10, 2021, a transcript from which will be entered into the record. We REVERSE. 1 We use the word “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42. Appellant identifies the real party in interest as “E. I. Du Pont De Nemours and Company” (Appellant’s June 19, 2020 Appeal Brief (Appeal Br.) 2). Appeal 2021-001892 Application 12/663,848 2 STATEMENT OF THE CASE Appellant’s disclosure “relates to a method for protecting an animal from a parasitic pest and parasitic pest infestation” (Spec.2 1:4-5). Appellant’s claim 27 is reproduced below: 27. A method for protecting a mammal from fleas, which comprises orally administering a dosage of about 10 mg/kg to about 100 mg/kg of mammal body weight of an isoxazoline compound the following formula: Compound 3 or a pharmaceutically acceptable salt thereof to the mammal, whereby the dosage is sufficient to protect the mammal from fleas at least 24 hours after oral administration and whereby the mortality to the fleas is at least 50%. (Appeal Br. 52.) 2 Appellant’s December 10, 2009 Specification. Appeal 2021-001892 Application 12/663,848 3 Grounds of rejection before this Panel for review: I. Claims 27-31 stand rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Mita ’617,3 ’921 Spec.,4 Hall,5 Snyder,6 Jeannin,7 Schrider,8 and Yeruham.9 II. Claims 27-31 stand rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Mita ’617, ’921 Spec., Hall, Snyder, Jeannin, Schrider, Patel,10 and Yeruham. III. Claims 27-31 stand rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Mita ’617, ’921 Spec., Mita ’089,11 Hall, Snyder, Jeannin, Schrider, and Yeruham. ISSUE Does the preponderance of evidence relied upon by Examiner support a conclusion of obviousness? FACTUAL FINDINGS (FF) FF 1. Mita ’617 “relates to a novel isoxazoline-substituted benzamide compound and the salt thereof, and a pesticide characterized by containing 3 Mita et al., US 2007/0066617 A1, published Mar. 22, 2007. 4 Mita et al., Application No. 11/514,921, filed Sept. 5, 2006, Specification (cf. Mita ’617). 5 Hall, US 2001/0011065 A1, published Aug. 2, 2001. 6 Snyder, US 6,664,237 B1, issued Dec. 16, 2003. 7 Jeannin et al., US 6,162,820, issued Dec. 19, 2000. 8 Schrider et al., US 3,968,207, issued July 6, 1976. 9 I. Yeruham et al., Ctenocephalides felis flea infestation in horses, 62 Veterinary Parasitology 341-43 (1996). 10 Patel, WO 2007/070606 A2, published June 21, 2007. 11 Mita et al., US 8,022,089 B2, issued Sept. 20, 2011. Appeal 2021-001892 Application 12/663,848 4 the compound as an active ingredient” (Mita ’617 ¶ 1; see also id. ¶ 9 (Mita ’617 discloses that a “compound according to . . . [its] invention has an excellent insecticidal and acaricidal activity” and “can provide a useful and novel pesticide”); id. ¶ 8 (Mita ’617 discloses compounds within the scope of its disclosed genus); Ans.12 3-4). FF 2. Mita ’617 discloses that “insects . . . that the compounds of . . . [its] invention can control concretely include,” inter alia, fleas (Mita ’617 ¶¶ 172, 173, 177; see Ans. 4). FF 3. Mita ’617 discloses: [W]hen the compound of . . . [its] invention is used for controlling ecto- or endoparasites of mammals and birds as domestic animals and pets, the effective amount of the compound of the present invention together with additives for formulations can be administered through[, inter alia,] oral administration” and that “[i]n administration, the compound . . . can be formed in an arbitrary dosage form that is suited for the administration route. (Mita ’617 ¶ 192; see Ans. 5 and 8). FF 4. Mita ’617 discloses that compounds within the scope of its disclosure may be applied to crops, wherein [a] dose of the compound . . . may vary depending on the place to be applied, time to be applied, method to be applied, crops to cultivate, etc., and in general, it is suitable in an amount of about 0.005 to 50 kg or so per a hectare (ha) as an amount to the effective ingredient. (Mita ’617 ¶ 191; see Ans. 9.) 12 Examiner’s November 19, 2020, Answer. Appeal 2021-001892 Application 12/663,848 5 FF 5. Mita ’617 discloses that compounds within the genus of its disclosure were tested, in vitro, for insecticidal activity against Ctenocephalides felis and that the following compounds showed an insecticidal rate of 80% or more among the compounds tested. The compounds of the present invention: No. 2-029*, 2-052, 3-151, 5-002, 5-003, 5-005, 5-007, 5-008, 5-012, 5-013, 5-023, 5-029, 5-037, 5-058, 5-071*, 5-072, 5-075*, 5-076*, 5-077, 5-086, 5-088*, 5-093*, 5-100*, 5-101*, 5-111*, 5-117, 5-121, 5-130* ,5-138, 5-139, 5-140*, 5-142*, 5-148*, 5-151*, 5-160*, 5-161 *, 5-165*, 5-174*, 5-182*, 5-184, 5-187, 5-188, 5-192, 5-205, 5-206, 5-209, 5-214*, 5-215*, 5-218, 5-219*, 5-223, 5-229, 5-230, 5-232, 5-234*, 5-235*, 5-236, 5-238, 5-240, 5-241 *, 5-243*, 5-245*, 5-247, 5-264, 5-274*, 5-287, 5-291, 5-294, 5-310*, 5-312, 5-313, 5-323, 5-354*, 5-356*, 5-359*, 5-360, 5-362, 5-376*, 5-377*, 5-378*, 5-379*, 5-383*, 5-384*, 5-387*, 5-389*, 5-390, 5-393, 5-399*, 5-401 *, 5-405*, 5-412*, 5-423*, 5-427*, 5-429*, 5-430*, 5-440*, 5-461*, 5-466*, 5-468*, 5-470*, 5-473, 5-474*, 5-475, 5-476, 5-477*, 5-478*, 5-480*, 5-487, 5-494*, 5-495-5-499, 5-579*, 5-587*, 5-623, 5-646*, 5-648*, 5-658, 6-020, 6-026, 6-033, 6-034, 6-035*, 6-043*, 6-046-6-049, 6-054, 6-055, 6-064*, 6-065*, 6-074, 6-092, 6-094, 6-095, 6-129, 6-130, 6-133, 7-002*, 7-004, 7-008*, 7-009[,] [wherein] . . . the indication of “*” shows that the insecticidal test was carried out with a treated dosage of 0.11 g/cm2. (Mita ’617 ¶¶ 526-529 (emphasis added); see Ans. 6 (Examiner finds that Mita ’617’s compound 5-151 “is the same compound structurally as the compound recited in . . . [Appellant’s] claim 27”); see also Ans. 6-7.); 1st Clark Decl.13 ¶ 11 (Clark states that “4-[5-(3,5-dichlorophenyl)-4,5-dihydro- 13 Declaration of Dr. Jeffrey N. Clark, signed May 10, 2018; see also the Declaration of Dr. Jeffrey N. Clark, signed May 20, 2019, (2nd Clark Decl.) Appeal 2021-001892 Application 12/663,848 6 5-(trifluoromethyl)-3-isoxazolyl]-2-methyl-N-[2-oxo-2-[(2,2,2- trifluoroethyl)-amino]ethyl)] benzamide, is fluralaner, the active ingredient in the product marketed as Bravecto®. This compound is identified as compound 5-151 in Mita [’61714]”); see also Huber Decl. ¶ 9 (Huber confirms Clark’s nomenclature of Appellant’s compound 3 and that it is the active ingredient in the product marketed as Bravecto®.).) FF 6. Examiner finds: The [0.11 g/cm2] dosage reported in [Mita ’617 ¶ 529] appears to be a misprinting on the part of the USPTO since the [S]pecification dated September 5th, 2006 in Application Serial No. 11/514,921 (the underlying application that resulted in the PGPub) recites the following on page 582 regarding the corresponding assay: In the interim, the indication of “*” shows that the insecticidal test was carried out with a treated dosage of 0.1 μg/cm2. (Ans. 7 (citing ’921 Spec. 582).) ¶ 3 (explaining that “[t]he word ‘Draft’ should have been deleted from the title” of the 1st Clark Decl.). 14 We acknowledge that the 1st Clark Decl. makes reference to Mita ’089, “Exhibit JNC-4” of the Declaration (see 1st Clark Decl. ¶ 10). Mita ’089, is a divisional of Application 11/514,921 (i.e. the ’921 Spec.), from which the US 2007/0066617 A1, publication (i.e. Mita ’617) is derived and, thus, all three documents have the same disclosure. Thus, we find that Clark’s statements, as they relate to the disclosure of Mita ’089, apply equally to the disclosure of Mita ’617 (see, e.g., 2nd Clark Decl. ¶ 7 (Clark declares “that Mita ’089 is a divisional of Mita ’617 and the ’921 application” and “The Teachings of Mita ’617 are cumulative to Mita ’089, Suffering from the Same Deficiencies, and do not Predict or Select for Compound 5-151’s In Vivo Oral Activity” (emphasis omitted).)). Clark and Huber refer to Mita ’089 and Mita ’617 collectively as the “Mita publications,” we, therefore, do the same (see 2nd Clark Decl. ¶ 28; see also Declaration of Dr. Scot Huber, signed May 16, 2018 (Huber Decl.) ¶ 14). Appeal 2021-001892 Application 12/663,848 7 FF 7. Clark declares that Mita’s: Contact assays measure the effect of the direct contact of selected compounds on the ectoparasite. These tests do not take into account any action of the compound or an active metabolite on the ectoparasite (oral or other systemic route) from an alternative test, the laboratory blood assay (flea membrane feeding assay), or a compound or active metabolite in a blood meal from the host treated with the compound, and there is no way to extrapolate these data from laboratory contact assays. Contact assays are primary screening assays that are routinely carried out during the early basic discovery stages of the investigation into putative pesticidal drugs. They indicate no support for possible activity in vivo. (1st Clark Decl. ¶ 22; see also id. ¶ 23 (Clark declares that “contact assays provide no information with respect to the potency, onset or duration of activity, metabolism/absorption or potential toxicity of a given compound after oral or systemic administration to an animal”); id. ¶ 24 (Clark declares that “[w]hether a compound that has been shown to be active in a simple laboratory contact assay would also be active in vivo . . . is inherently unpredictable” and that “[a] large number of variables are involved, none of which can be predicted or extrapolated based on information from a contact assay alone.”); 2nd Clark Decl. ¶¶ 12-19, 29; Huber Decl. ¶ 23 (Huber declares that “a simple contact assay of . . . [the type disclosed in the Mita publications] does not provide the skilled person with any information on whether the compound would be active against a particular ectoparasite when [orally] administered to a host animal (i.e. in vivo).”); see generally Huber Decl. ¶¶ 25-26 (discussing the differences between developing a non- system product versus a systemic product).) Appeal 2021-001892 Application 12/663,848 8 FF 8. Clark declares: Whether or not a compound has in vivo activity is determined by several factors. The compound must be capable of passing either intact or at least in an active form from the animal’s skin or from the gastrointestinal tract (if taken orally) into the target host (e.g. dog, cat) blood stream or tissue (exposure site to the ectoparasite), and thus be available for systemic distribution with in the host. For oral administration, the stability and solubility of the compound in the gastrointestinal tract will influence the extent to which a compound can be absorbed into the systemic circulation. When a compound is administered orally, it has to dissolve in the aqueous content of the stomach or small intestine (dissolution) and then be absorbed across the membranes of the gastrointestinal tract mucosal lining. Incomplete absorption lowers the proportion of compound able to reach the systemic circulation and thus compound concentration in the blood and subsequent exposure to the ectoparasite. Orally administered compounds may decompose in the fluids of the gastrointestinal lumen, be destroyed by stomach pH or be metabolized in the gastrointestinal tract itself before, during or after they pass through the mucosal lining cells. In addition, once a compound passes from the gastrointestinal tract into the hepatic portal vein, it may also be cleared from the body and/or metabolized by the liver to inactive forms even before entering the general circulation. The loss of compound due to metabolism or excretion as it passes through drug-eliminating organs (liver, kidney, etc.) for the first time is known as the first pass effect . . . . All of these factors affect how long it takes before a compound begins to clinically exert its activity, what blood concentration it might attain and how long it remains active. These factors also determine whether a contact active compound can ever be effective when given orally to an animal. (1st Clark Decl. ¶ 25; see also id. ¶ 26 (Clark declares that “active compound must . . . be bioavailable to an ectoparasite taking a blood meal from the host’s skin. A laboratory contact assay conducted in an isolated dish provides no information as to whether the compound is active by the oral or Appeal 2021-001892 Application 12/663,848 9 systemic route to either the ectoparasite directly or to the ectoparasite after taking a blood meal from the animal”); id. ¶ 32 (Clark declares that in order “[t]o be active in vivo, the compound must pass into the blood or tissue in a sufficient concentration from the route of administration (e.g. oral) to be therapeutically active when an ectoparasite takes a blood meal from the host animal,” which “cannot be predicted from an isolated laboratory ectoparasite contact assay.”); id. ¶ 33 (Clark declares that “active compound or its active metabolite must remain in the blood in a sufficient concentration and for a sufficient duration to be active for an extended period of time to be a viable product”.); 2nd Clark Decl. ¶ 23 (Mita provides “no correlation and no data . . . on how a compound which performs well in a contact assay would perform either in a membrane feeding assay or when given orally to animals.”); 2nd Clark Decl. ¶¶ 24-25.) FF 9. Huber declares there is simply not enough information available in Mita ’617 or Mita ’089 to give the skilled person any degree of confidence that the compounds would be capable of getting into the animal’s bloodstream in a sufficient concentration, let alone that the compounds would remain there for a long enough period to be effective against ectoparasites taking a blood meal from the animal. (Huber Decl. ¶ 27.) FF 10. Examiner finds that Mita ’617 “does not teach an explicit method or embodiment of protecting an animal from fleas at the instantly claimed dosage ranges or with the instantly recited compound” (Ans. 5; see also 1st Clark Decl. ¶ 38 (Clark declares that the Mita documents “provide[] no guidance to the skilled practitioner as to how to determine a dose rate for a compound administered orally that will be non-toxic to the host animal, Appeal 2021-001892 Application 12/663,848 10 while at the same time effectively killing fleas for 24 hours after oral administration of the compound.”); 2nd Clark Decl. ¶ 28 (Clark declares that Mita’s publications “do not provide either a general dosage range for in vivo administration to an animal or any in vivo data that the skilled person could use to determine an effective dose rate that would be non-toxic to the host animal while being efficacious against the parasite”)). FF 11. Clark declares that neither Mita ’617 nor Mita ’089 provide a: reasonable expectation of success as to a method for protecting a mammal from fleas by orally administering [Appellant’s] Compound 3 to the mammal, whereby the dosage is sufficient to protect the mammal from fleas at least 24 hours after oral administration and whereby the mortality to the fleas is about 50%[, as required by Appellant’s claimed invention]. (2nd Clark Decl. ¶ 22; see id. ¶ 29 (Clark declares that “the dose rate [in Appellant’s claimed method] must effectively kill at least 50% of the fleas for an extended duration of time (at least 24 hours).”); id. ¶ 29 (Clark declares that “this is not a situation where one is merely optimizing a specific dosage from a general range because no general range or in vivo data to determine a general range is provided in the Mita publications from which the skilled person could extrapolate a specific dose rate.”); see also id. ¶¶ 30-34; Huber Decl. ¶ 13 (Huber declares that “the Mita publications do not contain any of the information one skilled in the art would typically look for when evaluating a candidate for a method of administering (oral or otherwise) a drug candidate to an animal”); see also Huber Decl. ¶ 19 (citing Huber Decl. ¶¶ 14-18) (Huber declares that “the Mita publications are of a very generic nature, which provide insufficient guidance to the skilled person with respect to oral formulations.”).) Appeal 2021-001892 Application 12/663,848 11 FF 12. Hall discloses: [A] compound of formula wherein X and Y are, independently of one another, fluorine or chlorine, and Z is O or S. (Hall ¶¶ 1-2; see Ans. 10.) FF 13. Hall discloses: The compounds of formula (I) according to the invention are active substances for use in pest control offering very favourable biocidal efficacy and a very broad spectrum of activity of preventive and/or curative merit with favourable tolerability in warm-blooded animals, fish, and plants even at low concentrations. (Hall ¶ 58; see id. ¶ 60 (Hall discloses that its compounds are effective against fleas.); see also id. ¶¶ 190-191 (Hall exemplifies the “[i]n vitro effect [of compounds within the scope of its compound of formula I] on eggs, larvae or pupae of the cat flea Ctenocephalides felis.”); see Ans. 10- 11.) FF 14. Hall discloses that “[t]he compounds of formula (I) are usefully administered in a dose from 0.01 to 800 . . . mg/kg bodyweight with respect to the human subject and/or the host animal, oral administration being preferred,” that “[i]t is expedient to carry out the administration at regular intervals, e.g. every few days, weekly, or monthly,” and that “[t]he total dose can vary with the same active ingredient both between and within animal Appeal 2021-001892 Application 12/663,848 12 species, since the dose depends among other things on the weight and the constitution of the animal” (Hall ¶¶ 80-82; see Ans. 11-12). FF 15. Snyder discloses: A single-dose oral formulation for controlling an ectoparasite infestation on a dog or cat comprising an ectoparasiticidal amount of spinosad, or a physiologically acceptable derivative or salt thereof, and a physiologically acceptable carrier in a systemically effective oral dosage form selected from tablet, capsule or liquid suitable for administration once every at least 7 days at a dose of 10 to 100 mg of spinosad per kg of body weight. (Snyder 10:20-27; see Ans. 13 (citing Snyder 6, 7, and 9) (Examiner finds that Snyder discloses treating [cat flea] Ctenocephalides felis.).) FF 16. Jeannin discloses: Methods for removing parasites of vertebrates, and in particular arthropods, mainly insects and Arachnida, wherein an effectively parasiticidal amount of a compound of formula (I) in particular of fipronil, is administered to the animal via an administration route which makes possible systemic distribution and good absorption. (Jeannin, Abstr.; see Ans. 14.) FF 17. Jeannin discloses “[a] releasable composition with a dose of between 1 and 50 mg/kg . . . of body weight” (Jeannin 5:48-50; see Ans. 14). Appeal 2021-001892 Application 12/663,848 13 FF 18. Jeannin orally treated dogs, “experimentally infested” with fleas and ticks, with fipronil and found: A dose-duration of activity response was clearly demonstrated, i.e.: At the dose of 1 mg/kg, 100% flea control was obtained for 2 weeks and 100% tick control was obtained for 1 week. At the dose of 10 mg/kg, 100% flea control was obtained for 3 weeks and 100% tick control was obtained for 1 week. At the dose of 20 mg/kg, 100% flea control was obtained for 5 weeks and 100% tick control was obtained for 2 weeks. In addition to the dose-effect response demonstrated, this method made it possible to reveal that the systemic activity of fipronil by the oral route was superior in duration against the flea in comparison with the tick. (Jeannin 6:56-7:16; see generally Ans. 14-15.) FF 19. Schrider “relates to the use of O,O,O',O'-tetramethyl O,O'-thiodi-p- phenylene phosphorothioate insecticidal and acaricidal compositions, in particular as a pesticide to control ticks and fleas on cats and dogs” (Schrider 1:9-13; see Ans. 15). FF 20. Schrider discloses that “[t]he compound O,O,O',O'-tetramethyl O,O'- thiodi-p-phenylene phosphorothioate can be administered to dogs and cats in from 0.5 to 400 mg./kg. of body weight in a physiologically acceptable diluent, including cat and dog food, gelatin and the like” (Schrider 3:34-38; see Ans. 15). FF 21. Examiner relies on Yeruham to disclose that “Ctenocephalides felis felis, the cat flea, is found worldwide and has been reported to parasitize many species of wild and domestic animals, including dogs, cats, goats, sheep, cattle, chickens, bears, raccoons, ferrets, opossum and lizards” (Ans. 16 (emphasis omitted) (citing Yeruham 341 (citations omitted)); cf. 2nd Clark Appeal 2021-001892 Application 12/663,848 14 Decl. ¶ 51 (Clark declares that “Yeruham . . . is silent with respect to oral dosage rates for the isoxazoline compounds provided in the Mita publications . . . or any other compounds” and “provides no reasonable expectation of success as to” the method set forth in Appellant’s claimed invention); Huber Decl. ¶ 60 (Huber declares that “Yeruham is not relevant to the issues discussed herein and does not obviate the deficiencies found in the Mita publications and the remaining prior publications relied upon in the rejections”)). FF 22. Examiner relies on Mita ’089 to disclose: A method for controlling endo- or ecto-parasites of mammals or birds, the endo- or ecto-parasite being selected from the group consisting of[, inter alia,] . . . Ctenocephalides felis . . . the method comprising [orally] administering to a mammal or bird an effective amount of an endo- or ecto-parasiticide comprising as an active ingredient, 4-[5-(3,5-dichlorophenyl)-4,5-dihydro- 5-(trifluoromethyl)-3-isoxazolyl]-2-methyl-N-[2-oxo-2-[(2,2,2- trifluoroethyl)amino]ethyl)benzamide, an optically active form, or a salt thereof. (Mita ’089 572:30-42; see Ans. 23 (Examiner finds that Mita ’089’s 4-[5- (3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2- methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl)benzamide “is the same compound labeled as 1-151 in Mita” ’617.) FF 23. Clark Declares that Hall, Snyder, Jeannin, and Schrider (collectively the “Secondary Publications”) relate to compounds that are quite divergent in structure and mechanism of action both from each other and from the isoxazolines disclosed in the Mita publications. This structural divergence means that the compounds in the Secondary Publications form separate classes of compounds, both from each other and the Mita publications, and that: Appeal 2021-001892 Application 12/663,848 15 1) they would be expected to possess different physicochemical and pharmacokinetic/ pharmacodynamics properties; and 2) they achieve parasiticidal effects through divergent mechanisms of action . . . . In view of 1) and 2), one skilled in the art would not rely on the teachings of the Secondary Publications to provide any information whatsoever with respect to dosage ranges or efficacy of the isoxazoline compounds provided for in the Mita publications, whose mechanism of action was unknown at the time but expected by the skilled artisan to be different because of the divergent structure of this then novel class of compounds. Further, in view of the fact that each class of compounds has a divergent mechanism of action and would be expected to have different physiochemical and pharmacokinetic/pharmaco- dynamic properties, one skilled in the art would not see these prior publications as teaching “related methods.” (2nd Clark Decl. ¶ 35 (internal citation and footnote omitted); see also id. ¶¶ 37-50 (Clark separately addresses the limitations of each Secondary Publication.); Huber Decl. ¶¶ 41-49 (Huber separately addresses the limitations of each Secondary Publication); Huber Decl. ¶ 39 (Huber declares that “no one skilled in this art would look to a structurally dissimilar class of compounds in order to ascertain a dosage range for [Appellant’s] Compound 3 for any administrative route, let alone one for oral administration”).) FF 24. Patel “relates to certain isoxazolines, their N-oxides, salts and compositions suitable for agronomic and nonagronomic uses, including those uses listed below, and methods of their use for controlling invertebrate pests such as arthropods in both agronomic and nonagronomic environments” (Patel 1:4-7; see Ans. 43-44 (Examiner finds that Patel discloses isoxazoline compounds that are analogous to Mita ’617’s Appeal 2021-001892 Application 12/663,848 16 compounds “except where Patel teaches replacing one of the aromatic rings of . . . [Mita ’617’s compounds] with structures containing two nitrogen atoms in the ring.”)). FF 25. Patel discloses the oral administration of compounds within the scope of its disclosure to treat, inter alia, flea “afflict[ed] mammals and birds” (Patel 4:28-29; id. at 57:31-35; see Ans. 44). FF 26. Patel discloses that “[f]or oral administration to homeothermic animals, the daily dosage of a compound of the present invention typically ranges from about 0.01 mg/kg to about 100 mg/kg . . . of animal body weight” (Patel 77:29-31; see Ans. 44). FF 27. Clark discusses the differences between the compound used in Appellant’s claimed method and the compounds disclosed by Patel (see 2nd Clark Decl. ¶ 54) and declares: From these differences, I would expect the Patel compounds to exhibit different physicochemical and pharmacokinetic/ pharmacodynamic properties, which in turn would be expected to behave completely differently from the Mita compounds when administered orally to animals. . . . Therefore, I conclude no a priori prediction on how the Mita isoxazoline compounds would behave when administered orally to animals can be made from Patel. (id. ¶ 55; see id. (Clark declares that Patel, like the Secondary Publications and Yeruham, “provides no reasonable expectation of success as to” the method set forth in Appellant’s claimed invention.); see also id. ¶¶ 56-57; Huber Decl. ¶ 39 (Huber declares that “a person of skill in the art would not rely on dosage information for a compound with a very different structure because it would likely be a diversion and waste valuable time and resources”); see generally Huber Decl. ¶¶ 50-59.) Appeal 2021-001892 Application 12/663,848 17 FF 28. Huber declares that because the structure of [Appellant’s] Compound 3 is so different from the structures of the compounds of Hall, Snyder, Jeannin, Schrider and Patel, a person of skill in the art would not have had a reasonable expectation that a dosage range that is appropriate for one of the compounds would be reasonable for [Appellant’s] Compound 3. (Huber ¶ 39.) FF 29. Appellant’s “INDEX TABLE A” is reproduced below: Appellant’s INDEX TABLE A provides the structure of the ten compounds utilized in the exemplified tests, Tests A-D, set forth in Appellant’s Specification (see Spec. 65-68). Appeal 2021-001892 Application 12/663,848 18 FF 30. Appellant’s “Biological Examples of the Invention,” i.e. Tests A-D, are reproduced below: Test A For evaluating control of the cat flea (Ctenocephalides felis), a CD-1® mouse ( about 30 g, male, obtained from Charles River Laboratories, Wilmington, Mass.) was orally dosed with a test compound in an amount of 10 mg/kg solubilized in propylene glycol/glycerol formal (60:40). Two hours after oral administration of the test compound, approximately 8 to 16 adult fleas were applied to each mouse. The fleas were then evaluated for mortality 48 hours after flea application to the mouse. Of the compounds tested, the following compounds resulted in at least 50% mortality: 1, 2, 3 and 4. Test B For evaluating control of the cat flea (Ctenocephalides felis), a CD-1 ® mouse ( about 30 g, male, obtained from Charles River Laboratories, Wilmington, Mass.) was orally dosed with a test compound in an amount of 10 mg/kg solubilized in propylene glyco/glycerol formal (60:40). Twenty four hours after oral administration of the test compound, approximately 8 to 16 adult fleas were applied to each mouse. The fleas were then evaluated for mortality 48 hours after flea application to the mouse. Of the compounds tested, the following compounds resulted in at least 20% mortality: 1, 2 and 3. The following compounds resulted in at least 50% mortality: 2 and 3. Test C For evaluating control of the cat flea (Ctenocephalides felis), a CD-1 ® mouse ( about 30 g, male, obtained from Charles River Laboratories, Wilmington, Mass.) was subcutaneously dosed with a test compound in an amount of 10 mg/kg solubilized in propylene glycol/glycerol formal (60:40). Two hours after oral administration of the test compound, approximately 8 to 16 adult fleas were applied to each mouse. Appeal 2021-001892 Application 12/663,848 19 The fleas were then evaluated for mortality 48 hours after flea application to the mouse. Of the compounds tested, the following compounds resulted in at least 20% mortality: 1, 2 and 3. The following compounds resulted in at least 50% mortality: 1 and 3. Test D For evaluating control of the cat flea (Ctenocephalides felis), a test compound was solubilized in propylene glycol/glycerol formal (60:40) and then diluted in bovine blood to a final test rate of 30 ppm. The treated blood was placed in a tube, and the bottom of the tube was covered with a membrane. Approximately 10 adult cat fleas were allowed to feed through the membrane on the treated blood. The adult fleas were then evaluated for mortality 72 hours later. Of the compounds tested, the following compounds resulted in at least 500/o mortality: 1, 2, 3, 5, 6, 7, 8, 9 and 10. (Spec. 67-68.) FF 31. Clark declares that “there is nothing in the Mita publications that teaches or suggests that . . . [Appellant’s compound 3] would exhibit an early onset of action and a long duration of activity,” which Clark characterizes as unexpected properties that are disclosed in the “Test Examples” of Appellant’s Specification (2nd Clark Decl. ¶ 62 (citing 1st Clark Decl. ¶¶ 52-56 and Spec. 67-68 (Test Examples A-D))). ANALYSIS Rejection I: Examiner relies on Mita ’617 to disclose a genus of pesticidal compositions comprising an isoxazoline-substituted benzamide that may be administered to mammals through a variety of routes, including orally (see FF 1-4). Examiner finds that, through the use of an in vitro contact assay, Mita ’617 identified a subgenus of its isoxazoline-substituted benzamides Appeal 2021-001892 Application 12/663,848 20 that exhibited insecticidal activity against cat flea, Ctenocephalides felis (FF 5). Mita ’617 included within this subgenus compound 5-151, which is Appellant’s Compound 3 (id.). Examiner explains, however, that the rejection is not premised on choosing [Mita ’617’s] compound 5-151 to the exclusion of all others for further testing but rather that compound 5-151 would be among those that a person having ordinary skill in the art would choose for further optimization for utilities directed to, for instance, cat fleas. (Ans. at 52; see also id. at 54 (Examiner asserts “the rejection is not premised on the reference teaching that Compound 5-151 would be chosen to the exclusion of all others”); see also id. at 5 (Examiner reasons that because Mita ’617 discloses an “‘Insecticidal Test Against Ctenocephalid[es] felis’. . . a person having ordinary skill in the art would have been motivated to practice methods against fleas such as cat fleas”).)15 Examiner recognizes, however, that Mita ’617 “does not teach an explicit method or embodiment of protecting an animal from fleas at the instantly claimed dosage ranges or with the instantly recited compound” (FF 10). To make up for this deficiency, Examiner reasons that those of ordinary skill in this art would have found that the dosage range, length of protection, and flea mortality rate set forth in Appellant’s claimed invention, with respect to Compound 3, could have been determined through routine optimization (see Ans. 8 (Examiner finds that because Mita ’617 discloses that its compounds may be administered through a variety of routes including orally, “[i]t would appear to be the case that the instantly claimed limitation is directed to optimization of a result-effective variable”)). For 15 Examiner relies on ’921 Spec. to address an asserted typographical error in Mita ’617; see FF 6). Appeal 2021-001892 Application 12/663,848 21 support, Examiner turns to Hall, Snyder, Jeannin, and Schrider for disclosures of dosage ranges for a variety of insecticides that are unrelated to those disclosed by Mita ’617 (see Ans. 10-16; see FF 12-20). In addition, Examiner relies on Yeruham to disclose that “cat flea, is found worldwide and has been reported to parasitize many species of wild and domestic animals, including dogs, cats, goats, sheep, cattle, chickens, bears, raccoons, ferrets, opossum and lizards” (FF 21). Thus, based on the combination of Mita ’617, ’921 Spec., Hall, Snyder, Jeannin, Schrider, and Yeruham, Examiner concludes that, at the time Appellant’s invention was made, it would have been prima facie obvious to select any compound from Mita ’617’s list of compounds having “the highest activities in a flea assay,” including compound 5-151 (i.e. Appellant’s Compound 3), and then, with a reasonable expectation of success, optimize the selected compound to a dosage of about 10 mg/kg to about 100 mg/kg of mammalian body weight and orally administer a dose of the compound to a mammal to protect that mammal from fleas at least 24 hours after oral administration, whereby the mortality to the fleas is at least 50% (see Ans. 3-16). We are not persuaded. The method of Appellant’s claim 27 requires the oral administration Compound 3 to a mammal, in a dosage range of about 10 mg/kg to about 100 mg/kg of mammal body weight, wherein the dosage is sufficient to protect the mammal from fleas at least 24 hours after oral administration, whereby the mortality to the fleas is at least 50% (see Appeal Br. 52). Initially, we find that Examiner has not adequately explained why a person of ordinary skill would select Compound 3, i.e. 5-151, from the Appeal 2021-001892 Application 12/663,848 22 compounds listed in Mita ’617’s paragraph 528 (see FF 5). To the contrary, Examiner has, at best, asserted that the compounds listed in Mita ’617’s paragraph 528 would have served as a starting point for those of ordinary skill in this art to further screen for efficacy and, thus, somehow identify Appellant’s Compound 3 as effective for use in Appellant’s claimed method (see Ans. 52 (Examiner states that “the rejection is not premised on choosing [Mita ’617’s] compound 5-151 to the exclusion of all others for further testing but rather that compound 5-151 would be among those that a person having ordinary skill in the art would choose for further optimization for utilities.”); see also Appeal Br. 8 (Appellant contends that Examiner “provided no legitimate reason why a POSITA would first select Compound 5-151 from Mita ’617 for oral administration, and then look to the various other Secondary Publications for dosage guidance.”); Appeal Br. 9 (Appellant contends that “Compound 3 had never been orally administered, and the prior art was silent with respect to the proper dosage of Compound 3.”); Reply Br. 9 (“Mita ’617 provides no motivation for a POSITA to both select Compound 5-151 and then administer it orally to a mammal to protect it against fleas.”)). Even if, as Examiner asserts, those of ordinary skill in this art would limit the genus of Mita ’617’s compounds to those listed in its paragraph 528, which includes Appellant’s Compound 3, the evidence of record, as well as Examiner’s own reasoning, indicates that this disclosure provides nothing more than a starting point for further research into, inter alia, appropriate dosage amounts, whether the compound should be administered to plants and/or animals, and which of any number of different administrative methods should be utilized if administered to animals (see, Appeal 2021-001892 Application 12/663,848 23 e.g., FF 3-4; cf. FF 7-9 (Discussing the unpredictability of moving from an in vitro contact assay, as disclosed by Mita ’617, to an appropriate dosage for oral administration of a compound to protect a mammal from fleas at least 24 hours after oral administration and whereby the mortality to the fleas is at least 50% as required by Appellant’s claimed invention); FF 29- 30 (Establishing that compounds exhibiting activity in in vitro assays (Test D) are not necessarily effective in vivo (Tests A-C) and that, even if compounds show efficacy in vivo, the degree of efficacy differs among orally administered compounds (Tests A-B).); see also Appeal Br. 21 (Appellant contends “Mita ’617 provides no guidance for oral administration dosages” and “a POSITA would not consider it to disclose a dose range to be optimized.”)). Simply stated, Examiner’s reliance on Mita ’617 is founded on an impermissible “obvious to try” standard. As our reviewing Court explained: The admonition that “obvious to try” is not the standard under § 103 has been directed mainly at two kinds of error. In some cases, what would have been “obvious to try” would have been to vary all parameters or try each of numerous possible choices until one possibly arrived at a successful result, where the prior art gave either no indication of which parameters were critical or no direction as to which of many possible choices is likely to be successful. . . . In others, what was “obvious to try” was to explore a new technology or general approach that seemed to be a promising field of experimentation, where the prior art gave only general guidance as to the particular form of the claimed invention or how to achieve it. In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988) (citations omitted). For the reasons set forth above, both “kinds of error” discussed in O’Farrell are present in Examiner’s rejection. Thus, we find that the weight of the evidence on this record supports a conclusion that those of ordinary skill in Appeal 2021-001892 Application 12/663,848 24 this art would not have had a reasonable expectation of success in practicing Appellant’s claimed method based on Mita ’617’s disclosure (see FF 11 (Clark declares that Mita ’617 fails to provide those of ordinary skill in this art with a reasonable expectation of success in practicing Appellant’s claimed method); see id. (Clark and Huber both declare that there is insufficient guidance in Mita ’617 to arrive at Appellant’s claimed method); Appeal Br. 9-10 (Appellant contends “Mita ’617 . . . is inadequate because it provides no reason for a skilled artisan to select Compound 3 for further investigation, much less a reason for a skilled artisan to reasonably expect success when orally administering Compound 3 to protect a host animal from fleas”)). Further, as Clark makes clear, Hall, Snyder, Jeannin, and Schrider relate to compounds that “are quite divergent in structure and mechanism of action both from each other and from the isoxazolines disclosed in the Mita publications” and, thus, would have been expected by those of ordinary skill in this art to “possess different physicochemical and pharmacokinetic/ pharmacodynamics properties and . . . achieve parasiticidal effects through divergent mechanisms of action” (FF 23). As Huber explains, “no one skilled in this art would look to a structurally dissimilar class of compounds in order to ascertain a dosage range for [Appellant’s] Compound 3 for any administrative route, let alone one for oral administration” (id.). We find that the weight of the evidence falls in favor of Appellant (see Appeal Br. 24 (citing 2nd Clark Decl. ¶ 35; Huber Decl. ¶ 39) (Appellant contends that its “experts established, the Secondary Publications concern distinct classes of compounds” and Examiner erred by “incorrectly generaliz[ing], without Appeal 2021-001892 Application 12/663,848 25 support, that oral dosages between divergent classes of compounds are interchangeable. They are not, as the expert testimony established.”)). To be complete, we find that Examiner’s reliance on Yeruham fails to make up for the deficiencies in the combination of Mita ’617, ’921 Spec., Hall, Snyder, Jeannin, and Schrider (see FF 21). As Clark explains, “Yeruham . . . is silent with respect to oral dosage rates for the isoxazoline compounds provided in the Mita publications . . . or any other compounds” and “provides no reasonable expectation of success as to” the method set forth in Appellant’s claimed invention (id.; see also id. (Huber declares that “Yeruham is not relevant to the issues discussed herein and does not obviate the deficiencies found in the Mita publications and the remaining prior publications relied upon in the rejections”)). In sum, we find that the weight of the evidence on this record falls in favor of Appellant. Rejection II: This rejection differs from Rejection I only with respect to Examiner’s further reliance on Patel (see FF 24-26). Although Patel discloses isoxazoline compounds, Examiner recognizes that Patel’s isoxazoline compounds are structurally different from those disclosed in Mita ’617, including Appellant’s Compound 3 (see FF 24; see also Appeal Br. 44 (Appellant contends that although “Patel discloses an isoxazoline compound, that compound has significant structural differences from Compound 3” and “fails to provide an reasonable guidance for a starting point to determine an oral dose range to administer Compound 3 to an animal.”)). As Clark explains, because Patel’s compounds differ from Appellant’s Compound 3 Appeal 2021-001892 Application 12/663,848 26 “no a priori prediction on how the Mita isoxazoline compounds would behave when administered orally to animals can be made from Patel” (FF 27; see id. (Huber declares that “a person of skill in the art would not rely on dosage information for a compound with a very different structure because it would likely be a diversion and waste valuable time and resources”); see also FF 28 (Huber declares that a person of ordinary skill in this art would not have had a reasonable expectation of successfully determining a dosage range for Appellant’s Compound 3 based on the structurally different compounds disclosed by Hall, Snyder, Jeannin, Schrider, and Patel)). Thus, we find that the weight of the evidence on this record, supports a finding that Patel fails to make up for the deficiencies in the combination of Mita ’617, ’921 Spec., Hall, Snyder, Jeannin, Schrider, and Yeruham discussed above, with respect to Rejection 1. Rejection III: This rejection differs from Rejection I only with respect to Examiner’s further reliance on Mita ’089 (see FF 22). Specifically, Examiner relies on Mita ’089 to disclose, inter alia, a method of controlling cat flea comprising orally administering and effective amount of Appellant’s Compound 3 to a mammal in need thereof (see id.). Examiner does not, however, identify a disclosure in Mita ’089 that directs a person of ordinary skill in this art to orally administer a dosage of about 10 mg/kg to about 100 mg/kg of mammalian body weight to a mammal to protect that mammal from fleas at least 24 hours after oral administration, whereby the mortality to the fleas is at least 50%, as required by Appellant’s claimed invention. Appeal 2021-001892 Application 12/663,848 27 Thus, although Mita ’089 provides a reason to select Appellant’s Compound 3 for oral administration, it fails to make up for the deficiencies in the combination of Mita ’617, ’921 Spec., Hall, Snyder, Jeannin, Schrider, and Yeruham discussed above, with respect to the administration of a dosage of about 10 mg/kg to about 100 mg/kg of mammalian body weight to a mammal to protect that mammal from fleas at least 24 hours after oral administration, whereby the mortality to the fleas is at least 50%, as required by Appellant’s claimed invention. For the foregoing reasons, we find that Examiner failed to establish an evidentiary basis on this record to support the rejection of Appellant’s claimed invention. CONCLUSION The preponderance of evidence relied upon by Examiner fails to support a conclusion of obviousness. Rejection I: The rejection of claims 27-31 under 35 U.S.C. § 103(a) as unpatentable over the combination of Mita ’617, ’921 Spec., Hall, Snyder, Jeannin, Schrider, and Yeruham is reversed. Rejection II: The rejection of claims 27-31 under 35 U.S.C. § 103(a) as unpatentable over the combination of Mita ’617, ’921 Spec., Hall, Snyder, Jeannin, Schrider, Patel, and Yeruham is reversed. Rejection III: The rejection of claims 27-31 under 35 U.S.C. § 103(a) as unpatentable over the combination of Mita ’617, ’921 Spec., Mita ’089, Hall, Snyder, Jeannin, Schrider, and Yeruham is reversed. Appeal 2021-001892 Application 12/663,848 28 DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 27-31 103(a) Mita ’617, ’921 Spec., Hall, Snyder, Jeannin, Schrider, Yeruham 27-31 27-31 103(a) Mita ’617, ’921 Spec., Hall, Snyder, Jeannin, Schrider, Patel, Yeruham 27-31 27-31 103(a) Mita ’617, ’921 Spec., Mita ’089, Hall, Snyder, Jeannin, Schrider, Yeruham 27-31 Overall Outcome 27-31 REVERSED