DETAILED ACTION
Applicants’ arguments, filed 5 May 2026, 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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 § 112(a) – New Matter
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 43 and 45 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 43 is a new claim reciting a human whole serum. While the concept of serum from humans is disclosed by the original application as well as the concept of a whole serum, the original application does not appear to explicitly disclose a human whole serum.
Claim 45 recites a human engineered serum albumin and a human engineered serum albumin. Engineered serum albumin is disclosed, as is the concept of a human or mammalian serum albumin. However, engineered serum albumin that is also human does not appear to be explicitly disclosed.
In applicant’s response on 5 May 2026, applicant cites the following on page 4 of applicant’s response.
PNG
media_image2.png
244
626
media_image2.png
Greyscale
As an initial matter, the paragraph citations here appear to be incorrect, as paragraph [0120] of the specification as filed is a general teaching that modifications can be made to the invention and is unrelated to the subject matter of new claims 34-39. With that being said, paragraph [0120] of Lindsey et al. (US 2025/0073343 A1), which is the pre-grant publication of the instant application, does appear to be relevant, though this is paragraph [0104] of the instant application as filed. Relevant text from this paragraph has been reproduced below.
PNG
media_image3.png
158
604
media_image3.png
Greyscale
PNG
media_image4.png
150
604
media_image4.png
Greyscale
The above-reproduced text discloses whole serum; however, it also appears to disclose that when human serum is used, the human serum should be collected native human albumin rather than human whole serum. As such, the examiner understands the above-reproduced text to fail to provide adequate support for human whole serum.
The examiner notes that the instant specification discloses “recombinant/native mammalian albumin” as of page 8, bottom two lines. In this context, the examiner understands the phrase “recombinant” to provide support for the claimed term “engineered” because recombinant albumin would appear to have been formed from a gene that has been genetically engineered via recombinant DNA practices; therefore, recombinant albumin is engineered albumin. As such, claim 44 appears to be adequately supported. However, the instant application as filed does not appear to provide adequate support for recombinant or engineered human serum albumin; as such, this rejection applies to claim 45.
The examiner also reviewed paragraph 0027, and this paragraph does not appear to be relevant to the issue regarding serum albumin.
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, 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_image5.png
162
494
media_image5.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_image6.png
216
1040
media_image6.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_image7.png
146
386
media_image7.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_image8.png
44
996
media_image8.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 1, the claim requires a particular range of encapsulation efficiency. Iqbal teaches multiple examples with encapsulation efficiencies in the claimed range, as of Iqbal, page 181, Table 4, reproduced below.
PNG
media_image9.png
270
790
media_image9.png
Greyscale
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 31, Iqbal teaches the following, as of page 177, right column, relevant text reproduced below with annotation by the examiner.
PNG
media_image10.png
354
382
media_image10.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_image11.png
534
1474
media_image11.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_image12.png
102
380
media_image12.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_image13.png
138
496
media_image13.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_image14.png
256
704
media_image14.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_image13.png
138
496
media_image13.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_image13.png
138
496
media_image13.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_image15.png
338
1058
media_image15.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 and 43-45 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_image16.png
190
498
media_image16.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.
As to claim 16, Sleep is drawn to human serum albumin, as of Sleep, paragraph bridging pages 794-795.
As to claim 43, Sleep teaches the following as of page 794, right column, bottom paragraph, relevant text reproduced below.
PNG
media_image17.png
70
370
media_image17.png
Greyscale
The examiner understands this to refer to human whole serum.
As to claim 44, Sleep teaches combining albumin by addition of sodium octanoate and/or N-acetyltryptohan, resulting in a thermal protectant conformational change, as of Sleep, paragraph bridging pages 794-795. The examiner understands this to read on engineered human serum albumin because Sleep teaches engineering of human serum albumin with sodium octanoate and/or N-acetyltryptohan.
As to claim 45, this claim is rejected for essentially the same reason that claim 43 is rejected.
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_image18.png
510
410
media_image18.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_image19.png
370
402
media_image19.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
Applicant has presented arguments regarding the previously applied rejection, as of applicant’s response on 5 May 2026 (hereafter referred to as applicant’s response). These arguments are addressed below.
In order to provide context for applicant’s arguments, the examiner has reproduced various text from the “Response to Arguments” section of the prior office action mailed on 6 November 2025, specifically as of pages 30-32 of that office action.
Applicant has made the following arguments, as of applicant’s prior response on 10 September 2025, page 6, relevant text reproduced below.
PNG
media_image20.png
438
628
media_image20.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_image21.png
420
562
media_image21.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 applicant’s most recent response, applicant appears to dispute the idea that the method of Katare can best be equated with the third to last line of the above-reproduced table, and takes the position that the method of Katare should be equated with the fourth to last line of the above-reproduced table, as of applicant’s response, page 6, top paragraph. Applicant’s reasoning in support of this position is that Katare does not teach incubating with fetal bovine serum for as long as 24 hours. The experiment detailed on the fourth to last line of the above-reproduced table achieved an encapsulation efficiency of 6.67%; as such, applicant argues that the claimed encapsulation minimum encapsulation efficiency of 20% exceeds the 6.67% encapsulation efficiency disclosed in the above-indicated example. The examiner has reproduced relevant text below from page 6 of applicant’s response.
PNG
media_image22.png
164
634
media_image22.png
Greyscale
The examiner disagrees with this rationale because Katare appears to have achieved encapsulation efficiencies in the 28-70% range, as of Katare, page 181, Table 1. As such, the encapsulation efficiencies achieved by Katare appear to significantly exceed those of the fourth to last line of Table 6, reproduced above.
Applicant subsequently makes the following arguments on page 6, which have been reproduced below.
PNG
media_image23.png
130
624
media_image23.png
Greyscale
This argument is not persuasive in view of the analysis set forth above, indicating that Katare has achieved encapsulation efficiencies exceeding 17.39%.
Applicant then presents arguments regarding dependent claims, as well as secondary references, as of applicant’s response, bottom of page 6 through page 12 of applicant’s response. In these arguments, applicant argues that the dependent claim should be considered to be in condition for allowance for the same reason that the independent claim is alleged to be in condition for allowance. These arguments are not persuasive for the reasons set forth above.
Allowable Subject Matter
Claim 18 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
As relevant prior art, the examiner cites Iqbal, Katare, and Sung, which are discussed above and over which the instant claims have been rejected above. Nevertheless, unexpected results present in the instant application is sufficient to overcome the previously applied rejection of claim 18 for the reasons set forth below.
Data in the instant specification indicates that the presence of serum inside the particle would appear to result in improved release and delivery of IL-12 active agent, as of figure 14 of the instant application, which is reproduced below.
PNG
media_image24.png
367
397
media_image24.png
Greyscale
The data from which the above-reproduced figure was derived appears to come from Table 6 on pages 34-35 of the instant specification, which is reproduced below.
PNG
media_image25.png
370
556
media_image25.png
Greyscale
The last line of the above-reproduced table appears to represent the inventive example and the claimed invention. The sixth batch, as of the second to last line labeled “Surfactant*” is a comparative example was prepared with all of the sorbitan fatty acid ester, polyvinyl alcohol, and the polyoxyethylene sorbitan fatty acid ester (but lacking albumin), as of the instant specification, page 34, relevant paragraph reproduced below.
PNG
media_image26.png
258
604
media_image26.png
Greyscale
None of the examples in Iqbal are as close to the claimed invention as the comparative example indicated as “surfactant*” (i.e. the second to last line). This is at least because none of the examples of Iqbal have all of a hydrophilic active agent, the sorbitan fatty acid ester (which is an oil soluble surfactant) having been used as an emulsifier in the inner emulsion, and both polyvinyl alcohol (PVA) AND the water-soluble surfactant (i.e. polyoxyethylene sorbitan fatty acid ester) having been used in the outer emulsion. As such, applicant has succeeded in comparing the claimed invention to the closest prior art. See MPEP 716.02(e).
The examiner takes the position that applicant’s results have shown that the formation of a PLGA particle with a water-soluble protein cargo in combination with an oil-soluble surfactant, a water-soluble surfactant, PVA, and a serum/albumin achieves superior results as compared with the comparative example lacking albumin. Data in support of this position has been shown as of instant figure 14, as reproduced above. This figure shows unexpectedly and significantly greater release for the inventive example (which is labeled “surfactant +FBS” in that figure) as compared with the comparative example (which is labeled “Surfactant” in that figure). Iqbal does not appear to clearly motivate the skilled artisan to have used all of these ingredients together. Nothing in Iqbal appears to motivate the skilled artisan to have used all of PVA, a water-soluble surfactant other than PVA, and an oil-soluble surfactant. In contrast, the examples of Iqbal appear to teach the use of PVA as a water-soluble surfactant rather than using PVA in addition to a water-soluble surfactant other than PVA, which is the composition for which the instant application obtained unexpectedly beneficial results. As such, the composition of the instantly claimed invention differs from the compositions of Iqbal for this reason. Iqbal does not provide specific motivation for the skilled artisan to use both PVA and a separate water-soluble surfactant together; and this combination, along with the inclusion of the oil-soluble surfactant and the serum/albumin with the PLGA nanoparticle comprising a water-soluble therapeutic protein, appears to achieve unexpectedly superior results.
Additionally, the examiner notes here that the benefits obtained by applicant for using albumin in the inner phase differ from those envisioned by Iqbal. Iqbal indicates that the benefits of using albumin in the inner phase are for stabilizing the incorporated active agent, as of Iqbal, page 182, right column, section 4.2.3. These expected benefits differ from the desirable results obtained in the comparative testing detailed in the instant application, in which the inclusion of albumin in the inner phase of the composition resulted in higher release of the IL-12 active agent as compared with a comparative composition lacking said albumin in the inner phase of the composition. As such, the beneficial results obtained by applicant are different from what the skilled artisan would have expected the beneficial results to have been based upon the teachings of Iqbal. As such, the examiner understands the beneficial results obtained in the instant application to have been unexpected as the skilled artisan would not have expected such results based upon the teachings of Iqbal.
As such, the unexpected results present in the instant application are sufficient to overcome the previously applied rejection over Iqbal with respect to claim 18. The examiner notes that the rationale presented here is essentially the same as that presented in the office action mailed on 5 May 2026 in copending application 18/952404, especially as of the bottom of page 6 through page 10 of that office action. Additionally, the rationale provided here in regards to claim 18 does not appear to be commensurate with the full scope of instant claim 1 as it does not apply to the full scope of water-soluble synthetic polymers. See MPEP 716.02(d) regarding commensurateness in scope issues as they apply to an unexpected results determination.
Conclusion
Less than all claims are in condition for allowance.
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 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.
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, Sahana Kaup can be reached at (571)272-6897. 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
Prosecution Insights