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 .
Status of Application
The Amendments and Remarks filed on 03/30/26 are acknowledged.
Claims 1-26 were previously cancelled.
Claims 30, 31, 34, 35, 41, 48, and 49 were amended.
New claims 53-56 were added.
Claims 27-56 are pending and are included in the prosecution.
Information Disclosure Statement
The information disclosure statements (IDS) filed on 02/26/26 and 06/08/26 are acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the examiner is considering the information disclosure statements. Please see the attached copies of PTO-1449.
Response to Amendments/Arguments
Rejection of claims under 35 USC § 112(b)
In light of the amendment of claims 30, 31, 34, 35, 41, 48, and 49, the rejection of these claims under 35 U.S.C. 112(b) as being indefinite is withdrawn.
Maintained Objection to the Specification
The disclosure is again objected to because of the following informalities:
Although Applicant amended the Specification (on 03/30/26) to insert new paragraphs [0015]-[0030] after paragraph [0014] of the as-filed specification to provide descriptions of Figures 1-16, Applicant has not added the heading "BRIEF DESCRIPTION OF THE DRAWINGS." Based on MPEP § 608.01 (a) and (f), as well as 37 C.F.R. § 1.77(b), the Specification should be amended to recite the section heading "Brief Description of Drawings." Therefore, the objection to the specification is maintained.
New Objections necessitated by Amendment
Claim Objections
Claim 56 is objected to because of the following informalities: In claim 56, line 2, the period after the term “hydroxyanisole” should be replaced with a comma. A period should be added to the end of the sentence. MPEP 608.01(m) states: “Each claim begins with a capital letter and ends with a period.” Appropriate correction is required.
Notice for all US Patent Applications filed on or after March 16, 2013
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 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.
Updated Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
Claims 27-31, 39-41, and 50-51 are again rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wang et al. (CN 103 721 266 (A) – English Espacenet Translation – “Wang”).
Instant claim 27 is drawn to a process for preparing ivermectin particles having reduced particle size, wherein the process comprises incorporating ivermectin particles in a liquid medium comprising a mixture of an organic solvent with water, and subjecting the medium comprising the particles to mixing in a high shear mixer.
Wang teaches the process of preparation of drug-loaded microparticles of ivermectin and hydrogenated castor oil (HCO) and the suspension of the drug-loaded microparticles in an aqueous solution of poloxamer 407 (P407) to prepare an in-situ gelled injection containing ivermectin (Abstract, [0002], Examples 1-2, claims 1-5). The preparation method includes heating HCO and ivermectin in a low-boiling-point organic solvent, which includes ethanol, until completely dissolved, cooling to 40-55°C, distilling under reduced pressure to remove ethanol, obtaining solid matter, crushing it, passing it through a 40-mesh sieve to obtain the ivermectin microparticles ([0019], [0022]), and further mixing the drug-loaded microparticles with an aqueous solution comprising P407, shearing the mixture 3-5 times with a high shear homogenizer, grinding it with a colloid mill until the particle size is less than 80 µm, then grinding it with a sand mill until the particle size is less than 20 µm to obtain a thick suspension ([0019] (2) and [0022] (2)).
Regarding instant claims 27, 50, and 51, the limitations of a process for preparing ivermectin particles having reduced particle size are anticipated by the process of preparation of drug-loaded microparticles of ivermectin and HCO and the suspension of the drug-loaded microparticles in an aqueous solution of P407 to prepare an in-situ gelled injection containing ivermectin, wherein the particle size is less than 20 µm (Abstract, [0002], Examples 1-2, claims 1-5), as taught by Wang. The limitations of incorporating ivermectin particles in a liquid medium comprising a mixture of an organic solvent with water, and subjecting the medium comprising the particles to mixing in a high shear mixer are anticipated by the steps of heating HCO and ivermectin in a low-boiling-point organic solvent, which includes ethanol, until completely dissolved ([0019], [0022]), and further mixing the drug-loaded microparticles with an aqueous solution comprising P407, shearing the mixture 3-5 times with a high shear homogenizer, grinding it with a colloid mill until the particle size is less than 80 µm, then grinding it with a sand mill until the particle size is less than 20 µm to obtain a thick suspension ([0019] (2) and [0022] (2)), as taught by Wang.
Regarding instant claim 28, the limitations of the particles of ivermectin suspended in the liquid medium is anticipated by the thick suspension containing the particles of ivermectin ([0019] (2) and [0022] (2)), as taught by Wang.
Regarding instant claims 29-31, the limitations of the organic solvent are anticipated by ethanol ([0019], [0022]), as taught by Wang.
Regarding instant claim 39, the limitation the Dv (90) of the ivermectin particles after mixing of less than 60 microns is anticipated by the particle size of less than 20 µm ([0019] (2) and [0022] (2)), as taught by Wang.
Regarding instant claims 40-41, the limitations of the reduction in total impurities as measured by HPLC (% area) of the resulting ivermectin particles compared to the initial ivermectin particles of 10% or more (instant claim 40) and the total impurities of 3.0% or less, optionally 2.8% or less, or 2.7% or less (instant claim 41) are anticipated by the resultant ivermectin particle size of less than 20 µm ([0019] (2) and [0022] (2)), as taught by Wang. The recited limitations are properties of the ivermectin particles and are inherently present in the ivermectin particles taught by Wang. Please see MPEP 2112.01. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ 1655, 1658 (Fed. Cir. 1990.) The burden is shifted to Applicant to show that the prior art product does not possess or render obvious the same properties as the instantly claimed product.
Response to Arguments
Applicant’s arguments (see Pages 9-11, filed 03/30/26) with respect to the rejection of claims 27-31, 39-41, and 50-51 under 35 U.S.C. 102(a)(1) as being anticipated by Wang et al. (CN 103 721 266 (A) – English Espacenet Translation – “Wang”) have been fully considered but are not persuasive.
Applicant argues that: “In independent claim 1 of the present application ivermectin particles are incorporated in a mixture of an organic solvent and water, whereas in Wang the drug-loaded microparticles along with HCO is mixed with Poloxamer 407, which is a non-ionic surfactant and not a solvent as required by claim 1. It appears the examiner is combining both steps 1 and 2 of the disclosure in Wang ([0019] (2) and [0022] (2)), to arrive at claim 1 for assessing novelty … The key feature of Wang is that avermectin/HCO loaded microparticles are suspended in an aqueous solution nonionic surfactant P407. Whereas in claim 1 of the present invention, ivermectin particles are incorporated in an aqueous solution comprising a solvent, and not a surfactant.”
This is not persuasive because even though Wang teaches an aqueous solution of poloxamer 407 (P407) (Abstract, [0002], Examples 1-2, claims 1-5), an aqueous solution with the drug and the use of the organic solvent ethanol ([0019], [0022]) is also disclosed. Instant claims do not exclude the presence of a surfactant or P407.
Regarding instant claim 27, the limitations of incorporating ivermectin particles in a liquid medium comprising a mixture of an organic solvent with water, and subjecting the medium comprising the particles to mixing in a high shear mixer are anticipated by the steps of heating HCO and ivermectin in a low-boiling-point organic solvent, which includes ethanol, until completely dissolved ([0019], [0022]), and further mixing the drug-loaded microparticles with an aqueous solution comprising P407, shearing the mixture 3-5 times with a high shear homogenizer, grinding it with a colloid mill until the particle size is less than 80 µm, then grinding it with a sand mill until the particle size is less than 20 µm to obtain a thick suspension ([0019] (2) and [0022] (2)), as taught by Wang.
Applicant presents a table on Page 10 comparing Wang with independent claim 1 [sic] (presumed to be independent claim 27). Applicant argues that: “Wang does not teach high-shear mixing of a liquid medium as a micronization step for ivermectin. Agitation/stirring appears only as routine formulation handling, not as a size-reduction operation. Wang mainly focuses on in-situ gelling depot and controlled release; there is no explicit reduction of ivermectin particle size by high-shear wet milling/mixing.” Applicant argues that in the absence of any disclosure or teaching the step of subjecting a liquid medium comprising organic solvent with water and ivermectin to high shear mixer, the subject matter of claim 1 is inventive over Wang.
This is not persuasive because instant claim 27 does not exclude HCO (hydrogenated castor oil) or distillation. Instant claims also do not recite any specific particle size to distinguish over the microgranules taught by Wang. The process taught by Wang, including shearing the mixture 3-5 times with a high shear homogenizer, grinding it with a colloid mill until the particle size is less than 80 µm, then grinding it with a sand mill until the particle size is less than 20 µm to obtain a thick suspension ([0019] (2) and [0022] (2)), leads to the formation of microgranules which reads on the preparation of ivermectin particles having reduced particle size.
Therefore, the rejection of 12/31/25 is maintained.
Updated Rejections – necessitated by Amendment
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 of this title, 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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 32-33, 35, and 47-49 are again rejected and new claim 56 is also rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (CN 103 721 266 (A) – English Espacenet Translation – “Wang”), as applied to claims 27-31, 39-41, and 50-51 above, in view of Wang et al. (CN 104 666 244 (A) – English Espacenet Translation – “Wang ‘244”).
Instant claim 32 is drawn to a process according to claim 27 wherein the medium comprising the particles further comprises an antioxidant.
The teaching of Wang is discussed above.
Wang does not expressly teach the incorporation of an antioxidant.
Wang ‘244 teaches the process of preparing veterinary antiparasitic preparations (Abstract), wherein the antiparasitic drugs include ivermectin ([0010], Example 5 – [0051]-[0056], Example 9 – [0071]-[0073], and claim 1). Example 5 discloses the preparation of an ivermectin injections solution ([0051] including the steps of mixing ivermectin with a purity of 97%, carnauba wax, and ethyl oleate, dissolving the carnauba wax, cooling to room temperature, using a high-speed shear homogenizer at 12000-16000 r/min for 1 hour ([0051]-[0056]). Antioxidants including tert-butyl-4-hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) are disclosed ([0014]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the method of preparing drug-loaded microparticles of ivermectin by heating the ivermectin in an organic solvent, which includes ethanol, obtaining the ivermectin microparticles, further mixing the drug-loaded microparticles with an aqueous solution comprising P407, shearing the mixture 3-5 times with a high shear homogenizer, grinding it with a colloid mill until the particle size is less than 80 µm, then grinding it with a sand mill until the particle size is less than 20 µm to obtain a thick suspension, as taught by Wang, in view of the process of preparing veterinary antiparasitic preparations, wherein the antiparasitic drugs include ivermectin, the process includes the steps of mixing ivermectin with organic compounds, using a high-speed shear homogenizer at 12000-16000 r/min for 1 hour, and wherein antioxidants such as BHA and BHT are included, as taught by Wang ‘244, and produce the instant invention.
One of ordinary skill in the art would have been motivated to do this because the antioxidants preserve the stability of easily oxidizable components ([0014]) as taught by Wang ‘244.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Regarding instant claims 32-33, 35, 47-49, and 56, the limitations of the antioxidant would have been obvious over the BHA and BHT ([0014]), as taught by Wang ‘244. One of ordinary skill in the art would have found it obvious to add the antioxidants taught by Wang ‘244 to the particles of ivermectin of Wang in order to have antioxidant activity to preserve or stabilize the ivermectin particles. The temperature range of from 0°C to 25°C recited in instant claim 49 includes room temperature. One of ordinary skill in the art would have found it obvious to add the antioxidant at room temperature since this does not require additional equipment or controls.
Claims 32-34 and 47-49 are again rejected and new claims 53-54 are also rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (CN 103 721 266 (A) – English Espacenet Translation – “Wang”), as applied to claims 27-31, 39-41, and 50-51 above, in view of Wang et al. (CN 104 666 244 (A) – English Espacenet Translation – “Wang ‘244”) and Paulsen et al. (US 2009/0280159 A1 – “Paulsen”).
Instant claim 34 is drawn to a process according to claim 33 wherein the antioxidant is an alkyl paraben, optionally methyl paraben.
The teachings of Wang and Wang ‘244 are discussed above.
Wang and Wang ‘244 do not expressly teach the incorporation of an alkyl paraben or optionally methyl paraben.
Paulsen teaches the process for manufacturing chewable dosage forms for drug delivery to an animal (Abstract). The drug is ivermectin (Examples 1 and 2 – [0048]-[0049], claims 1, 25, and 26). The formulation contains a preservative which includes BHA, BHT (claims 1, 12, and 22) and methylparaben (claims 29 and 31).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the method of preparing drug-loaded microparticles of ivermectin by heating the ivermectin in an organic solvent, which includes ethanol, obtaining the ivermectin microparticles, further mixing the drug-loaded microparticles with an aqueous solution comprising P407, shearing the mixture 3-5 times with a high shear homogenizer, grinding it with a colloid mill until the particle size is less than 80 µm, then grinding it with a sand mill until the particle size is less than 20 µm to obtain a thick suspension, as taught by Wang, in view of the process of preparing veterinary antiparasitic preparations, wherein the antiparasitic drugs include ivermectin, the process includes the steps of mixing ivermectin with organic compounds, using a high-speed shear homogenizer at 12000-16000 r/min for 1 hour, wherein antioxidants such as BHA and BHT are included, as taught by Wang ‘244, further in view of the use of methylparaben as a preservative in a formulation containing ivermectin, as taught by Paulsen, and produce the instant invention.
One of ordinary skill in the art would have been motivated to include various antioxidants or preservatives known to be used with ivermectin including the BHA and BHT taught by Wang ‘244 ([0014]) as well as the BHA, BHT (claim 22) and methylparaben (claim 31) taught by Paulsen because the antioxidants preserve and enhance the stability of the formulations.
Regarding instant claims 32-34, 47-49, and 53-54, the limitations of the antioxidants would have been obvious over the methyl paraben (claim 31), as taught by Paulsen. One of ordinary skill in the art would have found it obvious to add the antioxidant taught by Paulsen to the particles of ivermectin of Wang in order to have antioxidant activity to preserve or stabilize the ivermectin particles. The temperature range of 0°C to 25°C recited in instant claim 49 includes room temperature. One of ordinary skill in the art would have found it obvious to add the antioxidant at room temperature since this does not require additional equipment or controls.
Claims 36-38 and 52 are again rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (CN 103 721 266 (A) – English Espacenet Translation – “Wang”), as applied to claims 27-31, 39-41, and 50-51 above, in view of Roberts et al. (US 4,413,118 – “Roberts”).
Instant claim 36 is drawn to a process according to claim 27 wherein the medium comprising the particles further comprises a stabilizer to minimize desolvation of the ivermectin.
The teachings of Wang are discussed above.
Wang does not expressly teach the incorporation of a stabilizer to minimize desolvation of the ivermectin.
Roberts teaches a process for preparing ivermectin comprising a step (d) of treating the ethanol solution with formamide and water to cause crystallization of the product (Col. 3, lines 1-4 and claim 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the method of preparing drug-loaded microparticles of ivermectin by heating the ivermectin in an organic solvent, which includes ethanol, obtaining the ivermectin microparticles, further mixing the drug-loaded microparticles with an aqueous solution comprising P407, shearing the mixture 3-5 times with a high shear homogenizer, grinding it with a colloid mill until the particle size is less than 80 µm, then grinding it with a sand mill until the particle size is less than 20 µm to obtain a thick suspension, as taught by Wang, in view of the process of preparing ivermectin comprising a step of treating the ethanol solution with formamide, as taught by Roberts, and produce the instant invention.
One of ordinary skill in the art would have been motivated to combine the methods taught by Wang and Roberts because they are both drawn to processes of preparing formulations of ivermectin. It is obvious to combine prior art elements according to known methods to yield predictable results. Please see MPEP 2141(III)(A). Furthermore, Roberts teaches that treating the ethanol solution with formamide and water causes crystallization of the product (Col. 3, lines 1-4 and claim 2).
Regarding instant claims 36-38, the limitations of the stabilizer would have been obvious over the formamide (Col. 3, lines 1-4 and claim 2), as taught by Roberts.
Regarding instant claims 36-38 and 52, the limitation of the organic solvent which is ethanol would have been obvious over the ethanol ([0019], [0022]), as taught by Wang. The limitation of the stabilizer comprising formamide would have been obvious over the formamide (Col. 3, lines 1-4 and claim 2), as taught by Roberts.
Claim 42 is again rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (CN 103 721 266 (A) – English Espacenet Translation – “Wang”), as applied to claims 27-31, 39-41, and 50-51 above, in view of Paulsen et al. (US 2009/0280159 A1 – “Paulsen”), and Roberts et al. (US 4,413,118 – “Roberts”).
Instant claim 42 is drawn to a process according to claim 27 wherein the medium comprises water; ethanol or isopropanol as the organic solvent; methylparaben as antioxidant, and formamide as a stabilizer.
The teachings of Wang are discussed above.
Wang does not expressly teach methylparaben as antioxidant, and formamide as a stabilizer.
The teachings of Paulsen with respect to the antioxidant methyl paraben and the teaching of Roberts with respect to formamide are discussed above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the method of preparing drug-loaded microparticles of ivermectin by heating the ivermectin in an organic solvent, which includes ethanol, obtaining the ivermectin microparticles, further mixing the drug-loaded microparticles with an aqueous solution comprising P407, shearing the mixture 3-5 times with a high shear homogenizer, grinding it with a colloid mill until the particle size is less than 80 µm, then grinding it with a sand mill until the particle size is less than 20 µm to obtain a thick suspension, as taught by Wang, in view of the use of methylparaben as a preservative in a formulation containing ivermectin, as taught by Paulsen, and the process of preparing ivermectin comprising a step of treating the ethanol solution with formamide, as taught by Roberts, and produce the instant invention.
One of ordinary skill in the art would have been motivated to combine the methods taught by Wang, Paulsen, and Roberts because they are all drawn to processes of preparing formulations of ivermectin. It is obvious to combine prior art elements according to known methods to yield predictable results. Please see MPEP 2141(III)(A).
Regarding instant claim 42, the limitation of the medium comprising the particles comprising water and ethanol would have been obvious over the steps of heating HCO and ivermectin in a low-boiling-point organic solvent, which includes ethanol, until completely dissolved ([0019], [0022]), and further mixing the drug-loaded microparticles with an aqueous solution comprising P407, shearing the mixture 3-5 times with a high shear homogenizer, grinding it with a colloid mill until the particle size is less than 80 µm, then grinding it with a sand mill until the particle size is less than 20 µm to obtain a thick suspension ([0019] (2) and [0022] (2)), as taught by Wang.
Regarding instant claim 42, the limitation of the methylparaben as antioxidant would have been obvious over the methyl paraben (claim 31), as taught by Paulsen.
Regarding instant claim 42, the limitation of the formamide as a stabilizer would have been obvious over the formamide (Col. 3, lines 1-4 and claim 2), as taught by Roberts.
Claim 43 is again rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (CN 103 721 266 (A) – English Espacenet Translation – “Wang”), as applied to claims 27-31, 39-41, and 50-51 above, in view of Wang et al. (CN 103 720 652 (B) – English Espacenet Translation – “Wang ‘652”).
Instant claim 43 is drawn to a process according to claim 27 wherein in the mixing step a suspension of ivermectin is recirculated at a range of rotations per minute of the high shear mixer of from 500 RPM to 9000 RPM.
The teachings of Wang are discussed above.
Wang does not expressly teach a range of rotations per minute of the high shear mixer of from 500 RPM to 9000 RPM.
Wang ‘652 teaches drug-loaded microparticles homogenized multiple times in a high shear homogenizer at an overlapping range of 5,000-10,000 rpm ([0020]) and ivermectin loaded microparticles homogenized at about 5000 RPM to obtain ivermectin injection with a particle size of less than 20 µm ([0032] and [0035]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the method of preparing drug-loaded microparticles of ivermectin by heating the ivermectin in an organic solvent, which includes ethanol, obtaining the ivermectin microparticles, further mixing the drug-loaded microparticles with an aqueous solution comprising P407, shearing the mixture 3-5 times with a high shear homogenizer, grinding it with a colloid mill until the particle size is less than 80 µm, then grinding it with a sand mill until the particle size is less than 20 µm to obtain a thick suspension, as taught by Wang, in view of the drug-loaded microparticles homogenized multiple times in a high shear homogenizer at an overlapping range of 5,000-10,000 rpm, as taught by Wang ‘652, and produce the instant invention.
One of ordinary skill in the art would have been motivated to combine the methods taught by Wang and Wang ‘652 because they are all drawn to the same processes of preparing microparticulate formulations of ivermectin. It is obvious to combine prior art elements according to known methods to yield predictable results. Please see MPEP 2141(III)(A).
Regarding instant claim 43, the limitation of a suspension of ivermectin recirculated at a range of rotations per minute of the high shear mixer of from 500 RPM to 9000 RPM would have been obvious over the drug-loaded microparticles homogenized multiple times in a high shear homogenizer at an overlapping range of 5,000-10,000 rpm ([0020]) and ivermectin loaded microparticles homogenized at about 5000 RPM to obtain ivermectin injection with a particle size of less than 20 µm ([0032] and [0035]), as taught by Wang ‘652.
Claim 44 is again rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (CN 103 721 266 (A) – English Espacenet Translation – “Wang”), as applied to claims 27-31, 39-41, and 50-51 above, in view of Wang et al. (CN 103 720 652 (B) – English Espacenet Translation – “Wang ‘652”) and Stuart et al. (WO 2021/022056 A1 – “Stuart”).
Instant claim 44 is drawn to a process according to claim 43 wherein a suspension of ivermectin is recirculated at a range of rotations per minute of the high shear mixer of from 1000 RPM to 2000 RPM.
The teachings of Wang and Wang ‘652 are discussed above.
Wang and Wang ‘652 do not expressly teach a range of rotations per minute of the high shear mixer of from 1000 RPM to 2000 RPM.
Stuart teaches methods of preparing compositions (Abstract). In one or more embodiments, the active agent is micronized so that the diameter of 90% of the particles (d(0.9)), is less than about 30 microns or less than about 20 microns, or less than about 10 microns ([00200]). The active agent ivermectin is disclosed ([00350]-[00351]). High shear mixing is used at a speed of 2000 rpm for a short period such as 10 minutes ([00754]), or a speed ranging from 1000 rpm or 2000 rpm (Page 346 - embodiment 4, lines 2-5).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the method of preparing drug-loaded microparticles of ivermectin by heating the ivermectin in an organic solvent, which includes ethanol, obtaining the ivermectin microparticles, further mixing the drug-loaded microparticles with an aqueous solution comprising P407, shearing the mixture 3-5 times with a high shear homogenizer, grinding it with a colloid mill until the particle size is less than 80 µm, then grinding it with a sand mill until the particle size is less than 20 µm to obtain a thick suspension, as taught by Wang, in view of the drug-loaded microparticles homogenized multiple times in a high shear homogenizer at an overlapping range of 5,000-10,000 rpm, as taught by Wang ‘652, further in view of high shear mixing at a speed of 2000 rpm or at a speed ranging from 1000 rpm or 2000 rpm, as taught by Stuart, and produce the instant invention.
One of ordinary skill in the art would have been motivated to combine the methods taught by Wang, Wang ‘652, and Stuart because they are all drawn to the same processes of preparing microparticulate formulations of ivermectin. It is obvious to combine prior art elements according to known methods to yield predictable results. Please see MPEP 2141(III)(A).
Regarding instant claim 44, the limitation of a suspension of ivermectin recirculated at a range of rotations per minute of the high shear mixer of from 1000 RPM to 2000 RPM would have been obvious over the high shear mixing at a speed of 2000 rpm ([00754]), or a speed ranging from 1000 rpm or 2000 rpm (Page 346 - embodiment 4, lines 2-5), as taught by Stuart.
Claims 45-46 are again rejected and claim 47 and new claim 55 are also rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (CN 103 721 266 (A) – English Espacenet Translation – “Wang”), as applied to claims 27-31, 39-41, and 50-51 above, in view of Hassan et al. (US 2011/0268659 A1 – “Hassan”).
Instant claim 45 is drawn to a process according to claim 27 wherein in the mixing step the medium comprising the ivermectin particles is recirculated at a temperature of from 0°C to 25°C.
The teachings of Wang are discussed above.
Wang does not expressly teach a temperature of from 0°C to 25°C.
Hassan teaches a method of high shear application in drug delivery (Abstract). In FIG. 2B, a therapeutic fluid 5 containing a drug are transported and stored in a vessel 20 with a temperature control unit 30; a pump 10 is configured for continuous or semi-continuous operation, and the temperature of the shear device 40 is maintained by the temperature control unit 30 which has the capacity to maintain a temperature between 0-100°C within ± 2°C ([0054]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the method of preparing drug-loaded microparticles of ivermectin by heating the ivermectin in an organic solvent, which includes ethanol, obtaining the ivermectin microparticles, further mixing the drug-loaded microparticles with an aqueous solution comprising P407, shearing the mixture 3-5 times with a high shear homogenizer, grinding it with a colloid mill until the particle size is less than 80 µm, then grinding it with a sand mill until the particle size is less than 20 µm to obtain a thick suspension, as taught by Wang, in view of the high shear processing of a therapeutic fluid containing a drug where the temperature is in the range of 0-100°C, as taught by Hassan, and produce the instant invention.
One of ordinary skill in the art would have been motivated to combine the methods taught by Wang and Hassan because both references are drawn to high shear processes for preparing drug particles. Furthermore, Hassan teaches that the high shear processing allows for creation of dispersion having a narrow distribution of the desired bubble size and particle size ([0034]). It is obvious to combine prior art elements according to known methods to yield predictable results. Please see MPEP 2141(III)(A).
Regarding instant claims 45-46 and 55, the limitations of a temperature of 0°C to 25°C (instant claim 45) and 0°C and 5°C (instant claims 46 and 47) would have been obvious over the temperature control unit 30 which has the capacity to maintain a temperature in the overlapping range of between 0-100°C within ± 2°C ([0054]), as taught by Hassan. According to MPEP 2144.05, “In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists.”
Response to Arguments
Applicant’s arguments (see Pages 11-12, filed 03/30/26) with respect to the following obviousness rejections have been fully considered but are not persuasive.
Rejection of claims 32-33, 35, and 47-49 under 35 U.S.C. 103 as being unpatentable over Wang in view of “Wang ‘244”
Rejection of claims 32-34 and 47-49 under 35 U.S.C. 103 as being unpatentable over Wang ‘244 and Paulsen
Rejection of claims 36-38 and 52 under 35 U.S.C. 103 as being unpatentable over Wang in view of Roberts
Rejection of claims 42 under 35 U.S.C. 103 as being unpatentable over Wang in view of Paulsen and Roberts
Rejection of claims 43 under 35 U.S.C. 103 as being unpatentable over Wang in view of Wang ‘652
Rejection of claims 44 under 35 U.S.C. 103 as being unpatentable over Wang in view of Wang ‘652 Stuart
Rejection of claims 45-46 under 35 U.S.C. 103 as being unpatentable over Wang in view of Hassan
Applicant argues that: “Office Action fails to establish the presence of each and every element of the presently pending claims. For the reasons set forth above, Wang does not teach or suggest each and every element of independent claim 1, and none of the various secondary references listed above cures the deficiencies of the primary reference, Wang.”
This is not persuasive because, as explained in detail above, Wang discloses each and every element of independent claim 27. The deficiencies in the dependent claims are addressed by the supporting references. Instant claims do not exclude the presence of a surfactant or a distillation process.
Therefore, the obviousness rejections of record are maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 extension fee 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 date of this final action.
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/ARADHANA SASAN/Primary Examiner, Art Unit 1615
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