DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.
Applicant's submission filed on 10 September 2025 has been entered, and the arguments presented therein have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Interpretation
For the purposes of examination under prior art, the abbreviation “PLGA” is understood to refer to poly(D,L-lactic acid co glycolic acid). See the instant specification on page 13, paragraph 0076.
For the purposes of examination, the term “nanoparticle” or “nanosphere” will be used interchangeably. These terms will be understood to refer to particles smaller than about 4-9 μm (i.e. 4000-9000 nm), which is the diameter of a capillary. See the instant specification on page 13, paragraph 0077.
For the purposes of examination under prior art, the examiner has proceeded under the assumption that the term “emulsifier” refers to a surfactant which stabilizes emulsions. As such, in the case of a prior art reference that teaches the term “emulsifier”, the examiner will proceed in examination with the understanding that the emulsifier taught by the prior art is a surfactant, as required by the instant claims.
With that being said, the examiner has proceeded in examination with the understanding that polyvinyl alcohol is not a surfactant. Support for this is obtained from page 9 of the specification, wherein the relevant text has reproduced below.
PNG
media_image1.png
146
606
media_image1.png
Greyscale
As such, the above-reproduced text would appear to indicate that polyvinyl alcohol differs from the second surfactant; therefore, the examiner does not understand polyvinyl alcohol to be a surfactant.
The examiner will proceed in examination with the understanding that the well-known trade name “Span 60” refers to sorbitan monostearate and the well-known trade name “Tween-80” refers to polyoxyethylene sorbitan monooleate.
Claim Rejections - 35 USC § 103 – Obviousness
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.
The factual inquiries 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.
Claim(s) 1, 15, 17-18, 31, 35, and 39-41 is/are rejected under 35 U.S.C. 103 as being unpatentable over Iqbal et al. (International Journal of Pharmaceutics, Vol. 496, 2015, pages 173-190).
Iqbal et al. (hereafter referred to as Iqbal) is drawn to double emulsion solvent evaporation for drug encapsulation, as of Iqbal, page 173, title and abstract. Iqbal teaches the following on page 175, right column, top paragraph.
PNG
media_image2.png
162
494
media_image2.png
Greyscale
The lipophilic emulsifier of Iqbal is understood to read on the required oil-soluble surfactant, and the hydrophilic emulsifier of Iqbal is understood to read on the required water-soluble surfactant. Iqbal teaches the use of PLGA as the polymer, an organic solvent, and polyvinyl alcohol (a synthetic polymer) as a stabilizer, as of Iqbal, various parts of the reference including page 176, Table 2, reproduced in part below.
PNG
media_image3.png
216
1040
media_image3.png
Greyscale
Regarding albumin, Iqbal teaches albumin as an excipient in the primary emulsion, as of Iqbal, page 182, right column, section 4.2.3, reproduced below with annotation by the examiner.
PNG
media_image4.png
146
386
media_image4.png
Greyscale
Iqbal also teaches evaporating the solvent, as of Iqbal, page 173, title and abstract.
As to claim 1, Iqbal is understood to teach all of the claimed requirements, but not in the same embodiment. While the prior art teaches all of the claimed components, the prior art is not anticipatory insofar as these components must be selected from various lists/locations in the prior art reference. It would have been prima facie obvious; however, to have selected the recited components from various lists/locations in the prior art reference and to have combined them together. This is because such a modification would have represented nothing more than the predictable use of prior art components according to their established functions. Combining separate prior art components (from a single prior art reference) according to known methods to yield predictable results is prima facie obvious. See MPEP 2143, Exemplary Rationale A.
As to claim 1, the examiner has generated the following table on the next page to clarify where in Iqbal various claim limitations are taught.
Limitation
Location in Iqbal
PLGA
At least page 176, Table 2
Oil-Soluble surfactant
175, right column, top paragraph (as lipophilic emulsifier)
Organic solvent
At least page 176, Table 2
Water-Soluble Therapeutic Protein
At least page 176, Table 2, teaching insulin, rhEGF, interferon alpha, tetanus toxoid, lysozyme
Serum albumin
page 182, right column, section 4.2.3 (albumin)
Water-soluble synthetic polymer
PVA (polyvinyl alcohol) on at least page 176, Table 2
Water-soluble surfactant
175, right column, top paragraph (as hydrophilic emulsifier)
As to claim 1, the claim requires a species specific engineered or native serum albumin. With regard to albumin as an excipient, Iqbal teaches albumin generically as of page 182, right column, section 4.2.3. However, elsewhere in the reference, Iqbal species bovine serum albumin, e.g. as of page 176 of Iqbal, though this is used as an active agent rather than as a therapeutic substance. Nevertheless, the skilled artisan would have understood bovine serum albumin to have been a type of albumin, and would have been motivated to have used bovine serum albumin as the albumin of the carrier of Iqbal, page 182, right column, section 4.2.3 in order to have predictably achieved the effects desired by Iqbal as of page 182 with a reasonable expectation of success.
As to claim 1, the claim requires a water-soluble therapeutic protein. Iqbal teaches various therapeutic agents that are proteins and that are water-soluble, such as tetanus toxoid, lysozyme, and insulin, as of Iqbal, page 176, relevant text reproduced below.
PNG
media_image5.png
44
996
media_image5.png
Greyscale
As to claim 1, the claim requires both a water-soluble surfactant and a water-soluble organic polymer in the second emulsion. Iqbal teaches a hydrophilic surfactant generally, as of page 175, right column, then separately teaches PVA (polyvinyl alcohol) on page 176, which is a hydrophilic polymer. Iqbal does not appear to teach an embodiment comprising both PVA and a hydrophilic surfactant together. Nevertheless, the skilled artisan would have been motivated to have combined these ingredients because they both appear useful for predictably stabilizing an emulsion with a reasonable expectation of success. Combining prior art elements according to known methods to yield predictable results is prima facie obvious. See MPEP 2143, Exemplary Rationale A.
As to claim 15, the bovine serum albumin (i.e. BSA) of Iqbal is understood to read on the required species-specific whole serum.
As to claim 17, Iqbal’s teaching of BSA on at least page 176 is understood to read on the required species-specific native serum albumin.
As to claim 18, Iqbal teaches polyvinyl alcohol as of page 176, Table 2.
As to claim 31, Iqbal teaches the following, as of page 177, right column, relevant text reproduced below with annotation by the examiner.
PNG
media_image6.png
354
382
media_image6.png
Greyscale
As best understood by the examiner, the above-reproduced text would have motivated the skilled artisan to have agitated the first (i.e. primary) emulsion.
As to claim 35, Iqbal, page 177, right column, relevant text reproduced above would have motivated the skilled artisan to have agitated the second emulsion.
As to claim 39, Iqbal teaches methylene chloride as an organic solvent as of page 176; this is a halogenated C1 solvent.
As to claims 40-41, Iqbal teaches encapsulating enzymes as of at least page 182, section 4.2.3.
Claim(s) 3-7, 13-14, and 40-42 is/are rejected under 35 U.S.C. 103 as being unpatentable over Iqbal et al. (International Journal of Pharmaceutics, Vol. 496, 2015, pages 173-190) in view of Zeng et al. (International Journal of Nanomedicine, Vol. 14, 2019, pages 6357-6369).
Iqbal is drawn to double emulsion PLGA nanoparticles which may comprise protein active agents. See the rejection above over Iqbal by itself.
Iqbal does not teach interleukin-12 (IL-12).
Zeng et al. (hereafter referred to as Zeng) is drawn to PLGA nanoparticles for the delivery of IL-12, as of Zeng, page 6537, title and abstract. Zeng teaches that the particles are made in the following manner, as of Zeng, page 6361, figure 1, reproduced below.
PNG
media_image7.png
534
1474
media_image7.png
Greyscale
As such, Zeng teaches PLGA nanoparticles comprising IL-12 as the active agent.
Zeng appears to differ from the claimed invention because Zeng does not appear to teach two separate surfactants.
It would have been prima facie obvious for one of ordinary skill in the art to have used IL-12 as the active agent in the composition of Iqbal. Iqbal teaches that double emulsion particles can be used for encapsulation of a wide variety of proteins, as of Iqbal, page 180, section 4.2.1. Zeng teaches encapsulation of IL-12 in a PLGA nanoparticle via double emulsion. As such, the skilled artisan would have been motivated to have encapsulated the IL-12 of Zeng into the nanoparticle of Iqbal for predictable delivery of IL-12 in order to have predictably treated diabetic retinopathy, as taught by Zeng, with a reasonable expectation of success.
As to claim 3, the IL-12 of Zeng is understood to read on the additional limitation of this claim.
As to claim 4, the IL-12 of Zeng is understood to read on the additional limitation of this claim.
As to claim 5, the IL-12 of Zeng is understood to read on the additional limitation of this claim.
As to claim 6, the IL-12 of Zeng is understood to read on the additional limitation of this claim.
As to claim 7, the IL-12 of Zeng is understood to read on the additional limitation of this claim.
As to claims 13-14, Zeng teaches PLGA with a 50:50 lactide:glycolide ratio, as of Zeng, page 6358, left column, bottom paragraph, reproduced below.
PNG
media_image8.png
102
380
media_image8.png
Greyscale
As to claim 40, the IL-12 of Zeng is understood to read on the additional limitation of this claim.
As to claim 41, the IL-12 of Zeng is understood to read on the additional limitation of this claim.
As to claim 42, the IL-12 of Zeng is understood to read on the additional limitation of this claim.
Note Regarding Publication Date of Zeng: As best understood by the examiner, the publication date of Zeng is 8 August 2019. Support for this position comes from the information disclosure statement (IDS) submitted on 8 August 2022 in parent application 17/830,615. The instant application appears to have an earliest effective filing date of 5 December 2019 based upon priority to provisional application 62/944,191. As such, Zeng was published less than a year prior to the earliest effective filing date of the instant application and is therefore prior art under AIA 35 U.S.C. 102(a)(1).
Claim(s) 3-8 and 40-42 is/are rejected under 35 U.S.C. 103 as being unpatentable over Iqbal et al. (International Journal of Pharmaceutics, Vol. 496, 2015, pages 173-190) in view of Fahmy et al. (US 2018/0200196 A1).
Iqbal is drawn to double emulsion PLGA nanoparticles which may comprise protein active agents. See the rejection above over Iqbal by itself.
Iqbal does not teach IL-12 or IL-2.
Fahmy et al. (hereafter referred to as Fahmy) is drawn to PLGA nanoparticles, as of Fahmy, title and abstract. Said nanoparticles may stimulate an immune response, as of Fahmy, title. The active agent in the nanoparticle of Fahmy may be IL-2, as of at least paragraph 0030, or IL-12, as of at least paragraph 0382.
As best understood by the examiner, Fahmy does not appear to teach two separate surfactants.
It would have been prima facie obvious for one of ordinary skill in the art to have used IL-2 and/or IL-12 as the active agent in the composition of Iqbal. Iqbal teaches that double emulsion particles can be used for encapsulation of a wide variety of proteins, as of Iqbal, page 180, section 4.2.1. Fahmy teaches encapsulation of IL-2 and/or IL-12 in a PLGA nanoparticle. As such, the skilled artisan would have been motivated to have encapsulated the IL-2 and/or IL-12 of Zeng into the nanoparticle of Iqbal for predictable delivery of IL-2 and/or IL-12 in order to have predictably increased an immune stimulatory response, as taught by Iqbal, with a reasonable expectation of success.
As to claim 3, the IL-2 and IL-12 of Fahmy are understood to read on the additional limitations of this claim.
As to claim 4, the IL-2 and IL-12 of Fahmy are understood to read on the additional limitations of this claim.
As to claim 5, the IL-2 and IL-12 of Fahmy are understood to read on the additional limitations of this claim.
As to claim 6, the IL-2 and IL-12 of Fahmy are understood to read on the additional limitations of this claim.
As to claim 7, the IL-12 of Fahmy is understood to read on the additional requirement of this claim.
As to claim 8, the IL-2 of Fahmy is understood to read on the additional requirement of this claim.
As to claim 40, the IL-2 and IL-12 of Fahmy are understood to read on the additional limitations of this claim.
As to claim 41, the IL-2 and IL-12 of Fahmy are understood to read on the additional limitations of this claim.
As to claim 42, IL-12 of Fahmy is understood to read on the additional limitations of this claim.
Claim(s) 9-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Iqbal et al. (International Journal of Pharmaceutics, Vol. 496, 2015, pages 173-190) in view of ICI Americas (“The HLB System a Time-Saving Guide to Emulsifier Selection.” ICI Americas Inc., Wilmington Delaware, Revised March 1980, pages 1-22).
Claim(s) 9-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Iqbal et al. (International Journal of Pharmaceutics, Vol. 496, 2015, pages 173-190) in view of Zeng et al. (International Journal of Nanomedicine, Vol. 14, 2019, pages 6357-6369), the combination further in view of ICI Americas (“The HLB System a Time-Saving Guide to Emulsifier Selection.” ICI Americas Inc., Wilmington Delaware, Revised March 1980, pages 1-22).
Claim(s) 9-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Iqbal et al. (International Journal of Pharmaceutics, Vol. 496, 2015, pages 173-190) in view of Fahmy et al. (US 2018/0200196 A1), the combination further in view of ICI Americas (“The HLB System a Time-Saving Guide to Emulsifier Selection.” ICI Americas Inc., Wilmington Delaware, Revised March 1980, pages 1-22).
Iqbal is drawn to a PLGA double emulsion used for encapsulation of various active ingredients including proteins. See the rejection above over Iqbal by itself. Zeng and Fahmy are drawn to particular active ingredients of IL-12 and IL-2. See the rejections above over Iqbal in view of Zeng and Iqbal in view of Fahmy. Iqbal also teaches the following, as of page 175, right column, top paragraph, reproduced below.
PNG
media_image9.png
138
496
media_image9.png
Greyscale
Iqbal does not teach sorbitan monostearate or polyoxyethylene sorbitan fatty acid ester.
ICI Americas Inc. (hereafter referred to as ICI Americas) is drawn to emulsifiers and the HLB (i.e. hydrophile-lipophile balance) system, as of ICI Americas, page 1, title. ICI Americas teaches low HLB emulsifiers as useful for water in oil emulsions and high HLB emulsifiers as useful for oil in water emulsions, as of ICI Americas, page 4, Table 1, reproduced below.
PNG
media_image10.png
256
704
media_image10.png
Greyscale
ICI Americas teaches that sorbitan monostearate is also known as Span 60 and is a low HLB emulsifier, as of ICI Americas, page 6, left column, bottom paragraph. ICI Americas teaches that polyoxyethylene sorbitan monolaurate, a polyoxyethylene sorbitan ester, is also known as Tween 20, as of ICI Americas, page 20, right column, and that Tween 20 has an HLB of 16.7, as of ICI Americas, page 20, left column, middle paragraph. ICI Americas also clarifies that lipophilic emulsifiers have low HLB and hydrophilic emulsifiers have high HLB, as of ICI Americas, page 3, right column.
ICI Americas does not teach a PLGA nanoparticle.
It would have been prima facie obvious for one of ordinary skill in the art to have used sorbitan monostearate as the first emulsifier of Iqbal, and polyoxyethylene sorbitan monolaurate as the second emulsifier of Iqbal. The first emulsifier of Iqbal is a lipophilic, and ICI Americas teaches that sorbitan monostearate (i.e. Span 60) is a lipophilic emulsifier useful for water in oil emulsions. As such, the skilled artisan would have been motivated to have used the sorbitan monostearate of ICI Americas in order to have predictably provided the inner water-in-oil emulsion of Iqbal with a reasonable expectation of success. Generally, it is prima facie obvious to select a known material (e.g. sorbitan monostearate, as of ICI Americas) for incorporation into a composition (that of Iqbal), based on its recognized suitability for its intended use (as a lipophilic emulsifier). See MPEP 2144.07.
It would have been prima facie obvious for one of ordinary skill in the art to have used the polyoxyethylene sorbitan ester of ICI Americas as the hydrophilic second surfactant in the composition of Iqbal. Iqbal teaches the use of a hydrophilic emulsifier. ICI Americas indicates that polyoxyethylene sorbitan esters, known as “Tweens” are hydrophilic emulsifiers useful for oil in water emulsions, as of ICI Americas, page 7, right column, top two lines and page 20, right column. As such, the skilled artisan would have been motivated to have used the polyoxyethylene sorbitan of ICI Americas in order to have predictably provided the outer oil-in-water emulsion of Iqbal with a reasonable expectation of success. Generally, it is prima facie obvious to select a known material (e.g. polyoxyethylene sorbitan “Tween” emulsifiers, as of ICI Americas) for incorporation into a composition (that of Iqbal), based on its recognized suitability for its intended use (as a hydrophilic emulsifier). See MPEP 2144.07.
As to claims 9-10, ICI Americas teaches sorbitan monostearate, as of page 6, left column, bottom paragraph, as the low HLB surfactant known as “Span 60.”
As to claim 11, ICI Americas teaches polyoxyethylene sorbitan fatty acid esters generically as of at least page 20, right column.
As to claim 12, ICI Americas teaches that surfactants numbered “80” are oleates, as of ICI Americas, page 7, left column, bottom paragraph. As such ICI Americas teaches Tween 80, as of at least page 10, left column, top paragraph; the examiner understands this to be polyoxyethylene sorbitan monooleate.
Claim(s) 9-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Iqbal et al. (International Journal of Pharmaceutics, Vol. 496, 2015, pages 173-190) in view of Azizi et al. (Journal of Polymer Research, Vol. 20:110, 2013, pages 1-14).
Claim(s) 9-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Iqbal et al. (International Journal of Pharmaceutics, Vol. 496, 2015, pages 173-190) in view of Zeng et al. (International Journal of Nanomedicine, Vol. 14, 2019, pages 6357-6369), the combination further in view of Azizi et al. (Journal of Polymer Research, Vol. 20:110, 2013, pages 1-14).
Claim(s) 9-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Iqbal et al. (International Journal of Pharmaceutics, Vol. 496, 2015, pages 173-190) in view of Fahmy et al. (US 2018/0200196 A1), the combination further in view of Azizi et al. (Journal of Polymer Research, Vol. 20:110, 2013, pages 1-14).
Iqbal is drawn to a PLGA double emulsion used for encapsulation of various active ingredients including proteins. See the rejection above over Iqbal by itself. Zeng and Fahmy are drawn to particular active ingredients of IL-12 and IL-2. See the rejections above over Iqbal in view of Zeng and Iqbal in view of Fahmy. Iqbal also teaches the following, as of page 175, right column, top paragraph, reproduced below.
PNG
media_image9.png
138
496
media_image9.png
Greyscale
Iqbal does not teach sorbitan monostearate or polyoxyethylene sorbitan fatty acid ester.
Azizi et al. (hereafter referred to as Azizi) is drawn to protein loaded PLGA nanoparticles made by water-in-oil-in-water emulsion, as of Azizi, page 1, title and abstract. Azizi uses Span 60 in the internal phase and Tween 80 in the external phase, as of Azizi, page 1, right column of abstract as well as paragraph bridging pages 2-3.
Azizi differs from the claimed invention for the following reason: As Azizi uses bovine serum albumin (abbreviated as BSA) as the model active agent, the embodiments of Azizi do not teach albumin along with a therapeutic substance separate from the albumin.
It would have been prima facie obvious for one of ordinary skill in the art to have used Span 60, as of Azizi, as the first emulsifier taught by Iqbal in the method of making the particle of Iqbal. It also would have been prima facie obvious for the skilled artisan to have used Tween 80, as of Azizi, as the second emulsifier in the method of making the particle of Iqbal. Azizi is drawn to making a PLGA particle for a w/o/w double emulsion, and uses Span 60 as the inner emulsion emulsifier and Tween 80 as the outer emulsion emulsifier. Iqbal is also drawn to a making a PLGA particle via a w/o/w double emulsion, and teaches a first emulsifier in the inner emulsion and second emulsifier in the outer emulsion, but is silent as to the chemical identity of these emulsifiers. As Azizi teaches Span 60 for the inner emulsifier and Tween 80 for the outer emulsifier, the skilled artisan would have been motivated to have used these compounds as the emulsifiers in the composition of Iqbal for predictably forming a w/o/w double emulsion with a reasonable expectation of success.
As to claims 9-10, the Span 60 of Azizi reads on the additional requirement of this claim.
As to claims 11-12, the Tween 80 of Azizi reads on the additional requirement of this claim.
Claim(s) 9, 11-12, 32, and 36 is/are rejected under 35 U.S.C. 103 as being unpatentable over Iqbal et al. (International Journal of Pharmaceutics, Vol. 496, 2015, pages 173-190) in view of Huang et al. (CN 104622795 A).
Claim(s) 9, 11-12, 32, and 36 is/are rejected under 35 U.S.C. 103 as being unpatentable over Iqbal et al. (International Journal of Pharmaceutics, Vol. 496, 2015, pages 173-190) in view of Zeng et al. (International Journal of Nanomedicine, Vol. 14, 2019, pages 6357-6369), the combination further in view of Huang et al. (CN 104622795 A).
Claim(s) 9, 11-12, 32, and 36 is/are rejected under 35 U.S.C. 103 as being unpatentable over Iqbal et al. (International Journal of Pharmaceutics, Vol. 496, 2015, pages 173-190) in view of Fahmy et al. (US 2018/0200196 A1), the combination further in view of Huang et al. (CN 104622795 A).
As an initial matter, Huang et al. (CN 104622795 A) has been written in Chinese. The examiner has provided an English language translation. All page and line citations are to the English translation, and the subject matter relied upon therein is understood by the examiner to have been present in the original Chinese document.
Iqbal is drawn to a PLGA double emulsion used for encapsulation of various active ingredients including proteins. See the rejection above over Iqbal by itself. Zeng and Fahmy are drawn to particular active ingredients of IL-12 and IL-2. See the rejections above over Iqbal in view of Zeng and Iqbal in view of Fahmy. Iqbal also teaches the following, as of page 175, right column, top paragraph, reproduced below.
PNG
media_image9.png
138
496
media_image9.png
Greyscale
Iqbal does not teach sorbitan monostearate or polyoxyethylene sorbitan fatty acid ester.
Huang et al. (hereafter referred to as Huang) is drawn to a microsphere-hydrogel composite system, as of Huang, title and abstract. Huang teaches the following, as of claim 7 on the last page of the English translation, which is reproduced below.
PNG
media_image11.png
338
1058
media_image11.png
Greyscale
As such, this method entails dissolving PLGA, Span 80 (which is a first surfactant), IGF-I (Which is a therapeutic substance), then combining with a water phase comprising Tween 80 (which is a second surfactant) and PVA (an abbreviation for polyvinyl alcohol), followed by removal of the solvents to form microspheres.
Huang differs from the claimed invention because (a) Huang does not teach the required serum and/or albumin, and (b) it is unclear if the microspheres of Huang are of a sufficiently small size to read on the required nanospheres.
It would have been prima facie obvious for one of ordinary skill in the art to have used the Span 80 and Tween 80 of Huang in the method of Iqbal. Iqbal is drawn to a method for preparing a double emulsion, and suggests the use of both a lipophilic emulsifier for the primary emulsion and a hydrophilic emulsifier for the secondary emulsion. Huang teaches specific materials which may be used for both the lipophilic emulsifier as well as the hydrophilic emulsifier. As such, the skilled artisan would have been motivated to have used Span 80, as of Huang, as the lipophilic emulsifier in the method of Iqbal in order to have predictably stabilized the primary emulsion of Iqbal with a reasonable expectation of success. The skilled artisan would also have been motivated to have used Tween 80, as of Huang, as the hydrophilic emulsifier in the method of Iqbal in order to have predictably stabilized the secondary emulsion of Iqbal with a reasonable expectation of success.
Additionally, the examiner notes that the method of Huang utilizes all of a lipophilic surfactant (i.e. Span 80), a hydrophilic surfactant (i.e. Tween 80) AND polyvinyl alcohol all in the same method. As such, the skilled artisan would have been motivated to have used all of these ingredients together in the same method to have predictably encapsulated a protein active agent in a PLGA particle via double emulsion with a reasonable expectation of success.
As to claim 9, Huang’s teaching of Span 80 reads on the required sorbitan fatty acid ester.
As to claim 11, Huang’s teaching of Tween 80 reads on the required polyoxyethylene sorbitan fatty acid ester.
As to claim 12, Huang’s teaching of Tween 80 reads on the required sorbitan monooleate.
As to claims 32 and 36, Huang teaches a 3000 rpm mixing speed. This mixing speed is lower than what is required by the instant claims. Nevertheless, 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)(A). In this case, the general conditions of forming a water in oil in water double emulsion with mixing are taught by the prior art. As such, it would not have been inventive for the skilled artisan to have discovered the optimum or workable ranges of mixing speed via routine experimentation.
Claim(s) 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Iqbal et al. (International Journal of Pharmaceutics, Vol. 496, 2015, pages 173-190) in view of Sleep (Expert Opinion in Drug Delivery, Vol. 12(5), 2014, pages 793-812).
Iqbal is drawn to a PLGA double emulsion used for encapsulation of various active ingredients including proteins. See the rejection above over Iqbal by itself. Iqbal teaches the following on page 182, right column, section 4.2.3, relevant text reproduced below.
PNG
media_image12.png
190
498
media_image12.png
Greyscale
As such, the skilled artisan would have been motivated to have used albumin in the formation of the primary emulsion.
Iqbal does not teach a species-specific engineered serum albumin.
Sleep is drawn to albumin and its application in drug delivery. Sleep teaches engineered albumins, as of page 793, paragraph entitled “Areas covered.” Sleep teaches that half-life can be increased via albumin engineering, as of Sleep, page 803, figure 3 and caption thereof.
Sleep does not teach a nanoparticle.
It would have been prima facie obvious for one of ordinary skill in the art to have substituted the engineered serum albumin of Sleep in place of the albumin of Iqbal, for use in the composition of Iqbal. Sleep teaches albumins engineered to extend half life. As such, the skilled artisan would have been motivated to have substituted the engineered albumin of Sleep in place of the non-engineered albumin of Iqbal in order to have predictably achieved the functions of serum albumin while predictably extending half-life with a reasonable expectation of success. The simple substitution of one known element (e.g. engineered albumin, as of Sleep) in place of another (e.g. “regular” albumin, as of Iqbal) in order to achieve predictable results (e.g. stabilizing an active ingredient) is prima facie obvious. See MPEP 2143, Exemplary Rationale B.
Claim(s) 32-34 and 36-38 is/are rejected under 35 U.S.C. 103 as being unpatentable over Iqbal et al. (International Journal of Pharmaceutics, Vol. 496, 2015, pages 173-190) in view of Kompella et al. (US 2017/0151266 A1).
Iqbal is drawn to a double emulsion and a method of making a double emulsion. See the rejection above over Iqbal by itself. Iqbal teaches methods of mixing and agitating the emulsion to help form the emulsion on page 177 of Iqbal, reproduced above.
Iqbal is silent as to the rate of agitation and the power level at which agitation occurs.
Kompella et al. (hereafter referred to as Kompella) is drawn to drug delivery formulations, as of Kompella, title and abstract. Kompella has prepared nanospheres in the following manner, as of paragraph 0122, reproduced below.
PNG
media_image13.png
510
410
media_image13.png
Greyscale
Kompella differs from the claimed invention because Kompella does not appear to specify a double emulsion as compared with a single emulsion.
It would have been prima facie obvious for one of ordinary skill in the art to have modified the method of Iqbal to have adopted the agitation rate, power level, and homogenization time taught by Kompella. Iqbal is drawn to a method for making an emulsion, but is silent as to how this agitation occurs. Kompella teaches that agitation may occur by homogenization at various speeds, as well as sonication at certain power levels for various time periods. As such, the skilled artisan would have been motivated to have homogenized at a certain value of rpm as well as a certain power level for a specific time period in order to have predictably formed the emulsion of Iqbal with a reasonable expectation of success.
As to claim 32, Kompella teaches agitating at 15,000 rpm as of paragraph 0122, reproduced above.
As to claim 33, Kompella teaches sonication at 30 W, as of the third to last line of paragraph 0122.
As to claim 34, Kompella teaches sonication for 1 minute, as of the sixth to last line of paragraph 0122. This is longer than the time at which sonication occurs in the instant claims. Nevertheless, 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)(A). In this case, the general conditions of forming an emulsion with agitation and sonication for a particular time and power level are taught by the prior art. As such, it would not have been inventive for the skilled artisan to have discovered the optimum or workable ranges of sonication time via routine experimentation. Additionally, Iqbal teaches that the particulars of the agitation process, such as the use of stirring or sonication, can be optimized depending upon the nature of the drug to be encapsulated and the intended particle size, as of Iqbal, page 177, right column, third to last line to page 178, left column, second line; this would have provided further motivation for the skilled artisan to have engaged in routine optimization.
As to claim 36, Kompella teaches agitating at 15,000 rpm as of paragraph 0122, reproduced above.
As to claim 37, Kompella teaches sonication at 30 W, as of the third to last line of paragraph 0122.
As to claim 38, this claim is rejected for essentially the same reason that claim 34 is rejected.
Relevant Prior Art – No Rejection
Sung Reference: As relevant prior art, the examiner cites Sung et al. (US 2007/0026005 A1).
Sung et al. (hereafter referred to as Sung) is drawn to a method of encapsulating IL-12 into a microsphere, as of Sung, title and abstract. Sung teaches the following, as of page 6, Example 1, reproduced below.
PNG
media_image14.png
370
402
media_image14.png
Greyscale
The above-reproduced method of Sung appears to differ from the claimed method for at least the following reason. In the above-reproduced method, the secondary emulsion is formed by emulsifying the primary w/o emulsion in an aqueous phase comprising polyvinyl alcohol. The examiner understands polyvinyl alcohol to be a water-soluble synthetic polymer. Sung does not teach a water-soluble surfactant separate from the water-soluble synthetic polymer. As such, the instant claims are not anticipated by Sung.
Additionally, it is unclear as to whether the particle size made by the method of Example 1 of Sung would have been sufficiently small to have read on the required nanospheres. This determination is made in view of the fact that Sung teaches microspheres rather than nanospheres. The term “microsphere” generally implies a particle size in the micron range, whereas the term “nanosphere” generally implies a particle size in the nanometer range, wherein a nanometer is three orders of magnitude smaller than a micron.
Katare Reference: As additionally relevant prior art, the examiner cites Katare et al. (European Journal of Pharmaceutical Sciences, Vol. 28, 2006, pages 179-188). Katare et al. (hereafter referred to as Katare) is drawn to tetanus toxoid loaded polylactic acid (PLA) particles, as of Katare, page 179, title and abstract. The nanoparticles of Katare comprise rat serum albumin, as of Katare, page 181, Table 1, which is abbreviated as “RSA.”
Katare differs from the claimed invention because (a) Katare teaches PLA rather than PLGA, and (b) Katare does not appear to teach the first and second surfactants. As such, the instant claims are not anticipated by Katare. Nevertheless, the teachings of Katare are relevant because they explain the purpose of adding albumin in the synthesis of the particles. Said albumin would appear to improve the encapsulation efficiency; see Katare, page 182, left column.
Response to Arguments Regarding Obviousness Rejections
Applicant has presented arguments regarding the previously pending obviousness rejections, as of applicant’s response on 10 September 2025 (hereafter referred to as applicant’s response). These arguments are addressed below.
Applicant has made the following arguments, as of applicant’s response, page 6, relevant text reproduced below.
PNG
media_image15.png
438
628
media_image15.png
Greyscale
In applicant’s response, applicant has cited Table 6 of the instant application. The examiner has reproduced this table below with annotation by the examiner.
PNG
media_image16.png
420
562
media_image16.png
Greyscale
The examiner agrees that the inventive example, comprising both an oil soluble surfactant and fetal bovine serum, shows significantly superior results regarding encapsulation efficiency as compared with the two indicated comparative examples.
In order to overcome a prior art rejection based upon unexpected results, the claimed invention must be compared with the closest subject matter to actually exist in the prior art. See MPEP 716.02(e). As best understood by the examiner, Iqbal, page 175, top paragraph, can be considered to teach an example that, at best, corresponds to the comparative example on the second to last line of the above-reproduced table. As best understood by the examiner, Katare et al. (European Journal of Pharmaceutical Sciences, Vol. 28, 2006, pages 179-188), which was cited on pages 35-36 of the prior office action mailed on 11 June 2025, can at best be considered to correspond to the comparative example on the third to last line of the above-reproduced table. As such, applicant has successfully compared the claimed invention to the closest subject matter to actually exist in the prior art.
In order to overcome a prior art rejection based upon unexpected results, the burden is on applicant to show that the results are unexpected and significant. See MPEP 716.02(b)(I). It is the examiner’s position that the dramatic increase in encapsulation efficiency from 35.71% in the closest comparative example to 87.54% in the inventive example meets this burden.
The examiner additionally takes the position that the above-indicated results are not expected beneficial results, as discussed in MPEP 716.02(c)(II). The examiner notes that Katare does teach that serum albumin results in improved encapsulation efficiency. However, there is no indication in Karate that serum albumin in combination with a oil-soluble and water-soluble surfactant would have resulted in superior encapsulation efficiency as compared with serum albumin in the absence of the oil-soluble and water-soluble surfactant.
Additionally, unexpected results must be commensurate in scope with the claimed invention. See MPEP 716.02(d). In this case, applicant’s data appears to be specific to IL-12 as the water-soluble therapeutic protein, Span 60 (i.e. sorbitan monostearate) as the lipophilic surfactant, Tween 80 (i.e. polysorbate 80) as the hydrophilic surfactant, and fetal bovine serum as the species-specific whole serum. There is no evidence that these results would have been applicable to the full scope of claim 1 in view of the differences in chemical structure between the different water-soluble therapeutic proteins, surfactants, and serum/albumins.
Applicant has presented additional arguments regarding the dependent claims on pages 7-11 of applicant’s response. Applicant argues that the dependent claims should not be rejected for essentially the same reason that the independent claim should not be rejected, and that any cited secondary reference does not cure the problems of the primary reference. These arguments are not persuasive because the primary reference is not deficient for the reasons set forth above.
The examiner has presented a proposed examiner’s amendment at the end of the office action.
Withdrawn Double Patenting Rejection
Previously in the prosecution history, the instant claims were rejected on the grounds of provisional non-statutory double patenting over the claims of copending application 18/952,404. This rejection has been withdrawn because the claims of the ‘404 application do not appear to recite the double emulsion process required by the instant claims. In other words, the claims of the ‘404 application do not recite first forming a primary water in oil emulsion, then emulsifying that emulsion in a secondary aqueous phase. There would have been no motivation for the skilled artisan to have further included this feature based upon the claim requirements of the claims of the ‘404 application.
Proposed Examiner’s Amendment
The examiner proposes amending the claims in the following manner to overcome the applied rejection.
Claim 1 (Proposed Amendment): A method of encapsulating a water-soluble therapeutic protein in a poly (D,L-lactic acid-co-glycolic acid)(PLGA) nanosphere, comprising:
a) forming a first emulsion comprising i) PLGA, ii) an oil-soluble surfactant, iii) an organic solvent, and iv) a first aqueous phase comprising A) the water-soluble therapeutic protein and B) a species-specific whole serum, a species-specific engineered serum albumin, or a species-specific native serum albumin;
b) forming a second emulsion comprising i) the first emulsion and ii) a second aqueous phase comprising A) a water-soluble synthetic polymer and B) a water-soluble surfactant; and
c) evaporating the organic solvent from the second emulsion, thereby forming the PLGA nanosphere encapsulating the water-soluble therapeutic protein,
wherein the encapsulation efficiency of the water-soluble therapeutic protein is from 40% to 87.54%.
No amendments to the dependent claims are proposed herein.
The examiner takes the position that the above-proposed amendment would appear to overcome the applied rejection. The examiner takes the position that, the skilled artisan would have been motivated to have increased encapsulation efficiency prior to the effective filing date. Nevertheless, there would have been no reasonable expectation that encapsulation efficiency could have been successfully optimized to have been in the claimed range. In order to properly support a rejection on the basis that an invention is the result of "routine optimization", the examiner must make findings of relevant facts, and present the underpinning reasoning in sufficient detail. The articulated rationale must include an explanation of why it would have been routine optimization to arrive at the claimed invention and why a person of ordinary skill in the art would have had a reasonable expectation of success to formulate the claimed range. See MPEP 2144.05(II)(B). In this case, in view of the data presented in the comparative examples of Table 6 of the instant specification, the skilled artisan would not have expected that encapsulation efficiency could have been improved beyond 35.71%. Nevertheless, data in the instant specification indicates that by using both a serum albumin and a combination of an oil-soluble surfactant and a water-soluble surfactant, encapsulation efficiency was unexpectedly increased. The skilled artisan would not have expected that encapsulation efficiency could have been increased to be in the claimed range with a reasonable expectation of success. The examiner notes that the minimum encapsulation efficiency of 40% is supported as of
Conclusion
No claim is allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ISAAC SHOMER whose telephone number is (571)270-7671. The examiner can normally be reached 7:30 AM to 5:00 PM Monday Through Friday.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Frederick F Krass can be reached at (571)272-0580. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
ISAAC . SHOMER
Primary Examiner
Art Unit 1612
/ISAAC SHOMER/ Primary Examiner, Art Unit 1612