DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Response to Amendment
The amendment filed September 21, 2026 has been entered. Claims 12-13 were amended, claims 2-4, 7, 10-11, 15-17, 21-32, 35-58 are canceled, and claims 62-63 are added. Applicant’s amendments have overcome the objections to the claims and specification as well as the 112b rejections and 102 rejections previously set forth in the Non-Final Office action mailed March 20, 2026. As such, these objections/rejections are hereby withdrawn.
Applicant’s arguments filed September 21, 2026 were fully considered but they were not persuasive. Maintained rejections
This application is a 371 of PCT/US2020/049457 filed September 4, 2020 and claims benefit of provisional application 62/896,944 filed September 6, 2019.
Claims 1, 5-6, 8-9, 12-14, 18-20, 33-34, and 59-63 are pending in this application.
Claim Interpretation
With respect to instant claim 12, which recites, “wherein the insect pollinators are administered the composition within the area to be treated”. The claim is interpreted to include wherein the same area encompasses administration to the pollinator itself.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 5-6, and 61-63 are rejected under 35 U.S.C. 103 as being unpatentable Wong (PLoS One, 2018, IDS filed August 10, 2023) as evidenced by Williamson (J. Experimental Biology, 2013, IDS filed August 10, 2023) and National Pesticide Information Center (Imidacloprid, 2018 cited in previous action).
Regarding claims 1, 5-6, and 61-63: Wong teaches certain phytochemicals, including quercetin and p-coumaric acid, are ubiquitous in the honey bee diet and are known to upregulate cytochrome P450 genes encoding enzymes that detoxify insecticides (abstract). Wong teaches treatment of honey bees exposed to 15, 45, 75, 105, and 135 ppb imidacloprid with 0.25 mM quercetin or 0.5 mM p-coumaric acid in a sucrose water diet (i.e. sucrose is a carbohydrate, pg. 5, para. 1). The amount of imidacloprid was chosen to mimic concentrations encountered by bees under field conditions (pg. 5, para. 1). Wong teaches that amelioration of pesticide toxicity by p-coumaric acid and quercetin is due to the induction of CYP9Q enzymes (pg. 3, para. 2). Wong teaches imidacloprid consumed was approximately 0.32-3.07 ng/bee/day (pg. 5, para. 1.). According to the instant specification 20 uL of 5 nM Imidacloprid causes learning and memory induced impairment (pg. 60, lines 25-27, pg. 62, lines 10-31). Williamson discloses sublethal amounts of imidacloprid ranging from 10 nmol/L to 100 nmol/L (1.3 ng-10.3 ng) can cause cognitive dysfunction (pg. 1800, col. 2, last para., pg. 1801, col. 2, last para). Wong teaches in sublethal diets 15 ppb (15 ug/L) imidacloprid concentrations, honeybees were administered p-coumaric acid and quercetin that reduces hazard risk (pg. 7, para. 3, pg. 8, fig. 1, pg. 6, table 2). National Pesticide Information Center discloses the molecular weight of imidacloprid is 255.7 g/mol (pg. 2, para. 2) and oral LD50 values for bees range from 3.7 ng to 40.9 ng per bee (pg. 13, para. 2). Given the molecular weight of imidacloprid 255.7g/mol and the following calculation (1x10-7mol/L(255.7g/mol))=2.557x10-5g/L=25.57ug/L), Williamson discloses sublethal amounts ranging from 2.557ug/L-25.57ug/L can cause cognitive dysfunction in honeybees. Thus Wong teaches administration of sublethal imidacloprid that is in sufficient dose to cause cognitive dysfunction in bees. Although Wong does not specifically disclose protection against impairment of cognitive function, the discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer (See MPEP 2112 (I)). Given that the doses of imidacloprid administered are sublethal yet enough to cause cognitive dysfunction and the doses of p-coumaric acid and/or quercetin are comparable to the doses claimed, the protection from cognitive dysfunction necessarily results from the method of Wong, absent evidence to the contrary.
Wong does not teach wherein the composition is administered prophylactically, i.e. before the insect pollinators are exposed to the pesticide as instantly claimed. As discussed above, Wong teaches co-administration of the p-coumaric acid or quercetin along with the pesticide imidacloprid. Wang does not teach wherein the composition is administered to insect pollinators between 1 hour and 10 days or 1 and 3 days before exposure to the pesticides.
However, Wong teaches consumption of imidacloprid and sugar water during the entire experimental period might negate the phytochemical “rescue effect” and that the protective effects of phytochemicals against imidacloprid build up over a longer period of time to provide beneficial effects against imidacloprid (pgs. 9-10, bridging para.). Wong teaches that protective effects of phytochemicals against imidacloprid build up over a longer period of time than within the 24-48 hour timeframe used in the acute toxicity bioassays (pg.9, last para.). Wong teaches that imidacloprid manifests itself through a delayed reaction compared to other pesticides and its metabolites persist longer and are more toxic than imidacloprid (pg. 10, para. 1). Wong teaches that competition between phytochemicals and pesticides for access to the enzyme catalytic sites may reduce the beneficial effects of phytochemicals (pg. 9, para. 3). Wherein administration time has an impact on the protective effects of phytochemicals to detoxify pesticides, and the prior art suggests greater than 48 hours is required for effective protection, time of administration is a result effecting variable. Where 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. (SEE MPEP 2144.05 (II).
Taken together it would have been prima facie obvious to a person of ordinary skill in the art to modify the method of Wong such that the quercetin/p-coumaric acid formulation is administered prophylactically greater than 48 hours, before the insect pollinators are exposed to the pesticide formulation as suggested by Wong. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success in in order to build up protective effects against imidacloprid as suggested by Wong. This method would necessarily result in the claimed protective benefits considering the composition comprises the claimed ingredients in the claimed concentrations. Wherein the prior art teaches greater than 48 hours, a person of ordinary skill in the art could arrive at the claimed administration ranges as recited by instant claims 62-63 through routine optimization.
Claims 8-9, 12-14, 18-20, and 33-34 are rejected under 35 U.S.C. 103 as being unpatentable over Wong (PLoS One, 2018, IDS filed August 10, 2023), Williamson (J. Experimental Biology, 2013, IDS filed August 10, 2023), and National Pesticide Information Center (Imidacloprid, 2018, cited in previous action) as applied to claims 1, 5-6, and 61-63 above in view of Johnson (PLoS One, 2012, IDS filed August 10, 2023) as evidenced by Charreton (PLoS ONE, 2015, IDS filed August 10, 2023).
Regarding claims 8-9, 12-14, 18-20, and 33-34: As discussed above, Wong renders obvious the method of claims 1 and 5-6.
Wong does not teach wherein the area occupied by insect pollinators is also occupied with insect pests and exposing the pollinators to the pesticide by treating the area occupied by both pollinator and insect pest with the pesticide. Wong does not teach wherein the insect pollinators are administered the composition in the same area or separate area from the pesticide. Wong does not teach wherein the area is treated with a pesticide that is effective to reduce the number of pests, is lethal to insect pests and sublethal to insect pollinators.
However, Johnson teaches a method of protecting honey bees (i.e. insect pollinator) from imidacloprid or tau-fluvalinate (i.e. pesticide) comprising administering a bee candy composition (i.e. food for ingestion) comprising quercetin (abstract, pg. 3, table 1, pg. 6, col. 1, paras. 4-5, col. 2, paras. 3-4). Johnson teaches that quercetin is a flavonol that occurs widely in plant nectars, pollen and honey (pg. 3, col. 1, para. 2). The bees were fed the bee candy and treated topically with the pesticide at sub-lethal doses (i.e. between the LD25 and the LD50, pg. 6, col. 2, paras. 3-4). Johnson teaches the bees were treated topically with 3, 5, and 10 µg tau-fluvalinate or 0.005, 0.01, or 0.03 µg imidacloprid (pg. 6, col. 2, para. 4). Johnson teaches sublethal effects of pesticide exposure (e.g., neonicotinoids) are suspected of causing reductions in hive viability (pg. 1, col. 2, para. 1). According to Charreton, sublethal doses of tau-fluvalinate at 33 ng cause a loco-motor deficit in honeybees (pg. 1, abstract). Thus, the dose of Johnson is enough to cause cognitive (motor) impairment. Johnson teaches tau-fluvalinate is safely used in-hive by beekeepers to control Varroa mites (i.e. lethal to insect pests, sub lethal to pollinator, pg. 2, col. 1, para. 2). Johnson teaches quercetin significantly decreased the toxicity of tau-fluvalinate to bees (i.e. a protective effect, pg. 3, col. 1, para. 3, table 1). Based on the teachings of Wong and Johnson, a person of ordinary skill would recognize the benefit of treating honey bees with quercetin that may come into contact with pesticides applied to hives maintained by beekeepers.
Taken together, it would have been prima facie obvious to modify the method of Wong, such that an area occupied by the insect pollinator have been or will be treated with a pesticide, such as tau-flauvinate or imidacloprid to control insect pests is used in the method, such as a beehive maintained by beekeepers as taught by Johnson. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success in order to protect honeybees (sublethal) from the pesticide while controlling insect pests (lethal), such as Varroa mites. Wherein an entire hive is treated with pesticides, It would have been prima facie obvious to administer the composition within the area and outside the area treated with the pesticide in order to prevent these toxicological effects effectively.
Claims 59-60 are rejected under 35 U.S.C. 103 as being unpatentable over Wong (PLoS One, 2018, IDS filed August 10, 2023), Williamson (J. Experimental Biology, 2013, IDS filed August 10, 2023) and National Pesticide Information Center (Imidacloprid, 2018, cited in previous action) as applied to claims 1, 5-6, and 61-63 above in view of Krizkova (Interdisc Toxicol, 2009, cited in previous action).
Regarding claims 59-60: As discussed above, Wong renders obvious the method of claim 1. Wong teaches certain phytochemicals, including quercetin and p-coumaric acid, are ubiquitous in the honey bee diet and are known to upregulate cytochrome P450 genes encoding enzymes that detoxify insecticides. (pg. 1, background).
Wong does not teach wherein the phenolic compound is rutin.
However, Krizkova teaches that rutin is a glycosylated version of the aglycone quercetin and both can increase CYP activities (pg. 202, col. 2, last. Para. pg. 202, figure 1., pg. 203, figs. 2-3, col. 1, para. 1).). Both quercetin and rutin are considered flavonoids (pg. 202, fig. 1). Flavonoids as a general class are recognized in the art to modulate the activity of cytochromes P450 (pg. 204, col. 1, para. 1).
Taken together it would have been prima facie obvious to modify the method of Wong such that quercetin is replaced with rutin as taught by Krizkova. A person of ordinary skill in the art would have the motivation to do so as rutin is a glycosylated version of quercetin that is known to interact/modulate P450 pathways. A person of ordinary skill in the art would have had a reasonable expectation of success as the art recognizes upregulation of cytochrome P450 is beneficial to detoxify insecticides and rutin possesses this characteristic. Wherein rutin and quercetin are flavonoids capable of modulating cytochrome activities, it is prima facie obvious to substitute equivalents known for the same purpose (see MPEP 2144.06 (II)).
Response to Arguments
Applicant’s arguments filed September 21, 2026 have been fully considered but they are not persuasive.
On page 12 of Applicant’s response, Applicant argues that the inherency argument relied upon can only be invoked within strict limits. On page 13 of Applicant’s response, Applicant argues that the office has expressly found that pre-administration is not disclosed by Wong, and thus said cognitive protection said to flow necessarily cannot occur based on the method actually disclosed in Wong (pg. 13, para. 2). Applicant argues that Wong speculates that protective effects build up over a longer period of time, but does not actually specify doing any pre-administration (para. 3). On pages 13-14 of Applicant’s response, Applicant argues that an inherency finding fails where it rests on optimization rather than on what the prior art necessarily contains (bridging para.). On page 14 of Applicant’s response, Applicant argues that a skilled artisan could arrive at the claimed administration ranges through routine optimization (para. 2). Applicant argues that the office relies on routine optimization to supply the pre-administration protocol and then relies on inherency (para 2).
However, the pre-administration step itself is not motivated by routine optimization, but rather what is suggested by the prior art to build up a protective effect. The fact that applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. In other words, the recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention. (See MPEP 2145 (II)). The routine optimization referenced in the rejection is in relation to the specific time frame at which the pre-administration is to occur. The prior art suggests greater than 48 hours, and with respect to claims 62-63, could be interpreted at the very least of 2 days pre-administration, which falls within both time frames as recited by instant claims 62-63. Further optimization of this time frame for successful protective effects would be within the technical grasp of the skilled artisan.
On pages 14-15 of Applicant’s response, Applicant argues that the asserted modified method is not defined with sufficient specificity for any result to necessarily flow (bridging para.). Applicant argues the office refers only to greater than 48 hours, and no relationship between timing of administration and timing or concentration of pesticide exposure and no protocol by which the recited cognitive protection would be obtained (bridging para.). On page 15 of Applicant’s response, Applicant argues a method defined only as Wong with the timing optimized has no determinate outcome and a characteristic cannot flow from an undefined method (para. 1). Applicant argues that the office action supplies no data that preadministration at any particular interval necessarily preserves cognitive function, only the assertion that protection necessarily results because the same ingredients are present at comparable concentration (para. 2). Applicant argues that the identity and concentration of ingredients do not establish that cognitive protection necessarily flows from a protocol wherein the timing of administration has been changed (para. 2).
However, Wong teaches that the art recognizes the general protective effect of consuming phytochemicals found in honey, pollen, and beebread for honeybees and at low levels of imidacloprid may stem from their capacity to upregulate detoxifying P450s (pg. 9, para. 2). Wong teaches that it appears that protective effects of phytochemicals against imidacloprid build up over a longer period of time than within the 24–48 hour timeframe used here for acute toxicity bioassays (pg. 9, last para.). Based on the teachings of Wong a person of ordinary skill in the art would recognize the ability of preadministration in order to upregulate detoxifying P450s thereby building up the protective effect.
On pages 15-16 of Applicant’s response, Applicant argues that Wong demonstrates that phytochemicals enhanced honey bee survival at low imdacloprid concentrations but had a negative effect at higher concentrations, and that combination of p-coumaric acid and quercetin with imidacloprid increases honeybee HR (bridging para.). On page 16 of Applicant’s response, applicant argues that Wongs data establishes that the effects of the same phenolic compounds are not uniform and Wong reports worse outcomes across a substantial portion of the range within the scope of claim 1 (para. 2).
However, the scope of claim 1 is limited only by concentration of the flavonol (i.e. p-coumaric acid). Wong teaches the amount of imidacloprid was chosen to mimic concentrations encountered by bees under field conditions (pg. 5, para. 1). Wong teaches that amelioration of pesticide toxicity by p-coumaric acid and quercetin is due to the induction of CYP9Q enzymes (pg. 3, para. 2). Wong teaches imidacloprid consumed was approximately 0.32-3.07 ng/bee/day (pg. 5, para. 1.). Wong teaches in sublethal diets 15 ppb (15 ug/L) imidacloprid concentrations, honeybees were administered p-coumaric acid and quercetin that reduces hazard risk (pg. 7, para. 3, pg. 8, fig. 1, pg. 6, table 2). Williamson discloses sublethal amounts ranging from 2.557ug/L-25.57ug/L can cause cognitive dysfunction in honeybees. Wong teaches Quercetin alone and in combination with p-coumaric acid similarly enhanced longevity at 45 ppb imidacloprid (HR:0.81 and HR:0.77, respectively) (pg. 1, last para.). Thus a person of ordinary skill in the art would recognize the benefit of the phytochemicals to honeybees exposed to these levels of imidacloprid which as discussed above, are enough to cause cognitive dysfunction.
On page 16-17 of Applicant’s response applicant argues that Wong does not establish that pre-treatment administration is a result effective variable and does not even report that pretreatment increases protection from lethality, merely that under some dosage, protection from lethality builds over time of coincident administration with pesticide.
However, the pre-administration step itself is not motivated by routine optimization, but rather what is suggested by the prior art to build up a protective effect. The fact that applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. In other words, the recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention. (See MPEP 2145 (II)). The routine optimization referenced in the rejection is in relation to the specific time frame at which the pre-administration is to occur. The prior art suggests greater than 48 hours, and with respect to claims 62-63, could be interpreted at the very least of 2 days pre-administration, which falls within both time frames as recited by instant claims 62-63. Further optimization of this time frame for successful protective effects would be within the technical grasp of the skilled artisan.
On page 19 of Applicant’s response, Applicant argues Wong does not state measurement of learning, memory, sensory responsiveness, or motor activity and only enhanced survival and an approximately 30% increase in hazard ratio (para. 2). On page 19 of Applicant’s response, Applicant argues the claimed prophylactic method produced significant preservation of learning and memory following imidacloprid exposure (para. 3). Applicant argues these results were not confined to imidacloprid, but also with fipronil and deltamethrin (para. 4). The Examiner notes that on page 74 of the instant specification, flavonoids kaempferol and rutin and phenol p-coumaric acid were examined (lines 23-25). On page 20 of Applicant’s response, Applicant argues the instant application demonstrates different results from the survival benefit of Wong, and concerns a different functional property and the evidence therefore demonstrates a difference (para. 2). On page 20 of Applicant’s response, Applicant argues the unexpected cognitive protection has a nexus to the claimed prophylactic administration which differs from the simultaneous administration of Wong (para. 3). Applicant argues the persistence of protection, more than 36 hours after the last flavonoid dose following only a single day of administration, links the observed protection to a state established before pesticide exposure rather than to an interaction requiring contemporaneous presence of phytochemical and pesticide (para. 4). On pages 20-21 of Applicant’s response, Applicant argues the docking and molecularly dynamics corroborate the behavioral evidence at the receptor level and points to the declaration of Rivera, filed February 23, 2026 in which the timing of administration and persistence of protection and behavioral data are connected (bridging para.). On page 21 of Applicant’s response, Applicant argues that the unexpected cognitive result should be weighed independently of any survival benefit expected from Wong (para. 2). Applicant argues even assuming some survival benefit might have been expected, preservation of learning and memory addresses a separate functional consequence of pesticide exposure (para 2). Applicant argues the evidence presented demonstrates pesticides having distinct mechanisms of action and the protection offered by flavonoids extends to pesticides with different mechanisms of action (last para.). On pages 21-22 of Applicant’s response, Applicant argues the unexpected results are a result of the prophylactic method and provides sufficient weight to extend to the scope of claimed subject matter (bridging para.).
However, evidence was provided that states the amount of imidacloprid exposure contemplated by Wong is sufficient to exhibit cognitive impairment. Given that Wong teaches the composition detoxifies this pesticide, a person of ordinary skill in the art would expect this alleviate negative impacts, including those not recognized at the time of Wong, absent evidence to the contrary. While Wong is an experimental study, Wong specifically teaches that the amount of imidacloprid was chosen to mimic concentrations encountered by bees under field conditions (pg. 5, para. 1). A person of ordinary skill in the art would recognize the eventual application of the method to be a prophylactic one, as in field conditions honey bees are not meant to be directly administered pesticides. Wong supports this by stating pesticides such as imidacloprid have been a focus of attention in colony decline of the honey bee, wherein honey bees are exposed to the pesticide via the consumption of nectar and pollen (i.e. field conditions, pg. 2, introduction, para. 1). Furthermore, Wong suggests consumption of imidacloprid and sugar water during the entire experimental period might negate the phytochemical “rescue effect” and that the protective effects of phytochemicals against imidacloprid build up over a longer period of time to provide beneficial effects against imidacloprid (pgs. 9-10, bridging para.). Thus wherein it would have been obvious to administer the composition of Wong which anticipates the claimed composition, to honey bees prior to exposure to imidacloprid, a pesticide known in the art to cause cognitive impairment, the resulting decrease in cognitive impairment (or improvement thereof) necessarily results as a result of practicing the method. A person of ordinary skill in the art would recognize the benefit of administering these phytochemicals to honeybees that could be exposed to low amounts of imidacloprid for the benefit of improving survival, that necessarily reduces cognitive impairment caused by such exposure.
The Examiner also notes that unexpected results must also be commensurate with the scope of the claims (See MPEP 716.02(d). The instant specification demonstrates the therapeutic benefit of rutin or quercetin on imidacloprid exposure of honeybees (pg. 58, lines 5-16). The instant claims include prophylactically treating insect pollinators with one or more flavonols, a large class of possible compounds, and pesticides generally. Thus, even if the unexpected results were to be found persuasive, they would not be commensurate with the scope of the claims.
Applicant’s reply is considered to be a bona fide attempt at a response and is being accepted as a complete response. The 35 USC § 103 rejections are maintained for reason of record and foregoing discussion.
Conclusion
No claims are allowed in this action.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/S.L.G./Examiner, Art Unit 1693
/ANDREA OLSON/Primary Examiner, Art Unit 1693
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