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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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 Objections
Claim 1 is objected to because of the following informalities: Claim 1 numbers the various ingredients present in the composition with lowercase roman numerals; however, the numbering appears to skip from “iv)” to “vi)” and appears to skip “v).” As such, claim 1 is objected to because of incorrect numbering of the claim elements. See the following text reproduced below with annotation by the examiner.
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Applicant may correct this by adding the number “v)” prior to “a water-soluble synthetic polymer” as of the end of the fourth line of claim 1.
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.
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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. In contrast, polyvinyl alcohol is a water-soluble polymer, which is now required by claim 1.
The examiner also clarifies that claim 1 now recites a water-soluble synthetic polymer and a serum and/or albumin as a separate material. Even if, purely en arguendo, the albumin was to have been made synthetically, the examiner still interprets claim 1 such that the water-soluble synthetic polymer and the albumin are understood to be separate polymers. The examiner also understands the water-soluble therapeutic protein and the water-soluble synthetic polymer to be separate substances; this is the case even if, purely en arguendo, the water-soluble therapeutic protein was to have been made synthetically.
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.
Response to Arguments Regarding Claim Interpretation Issues
Applicant does not appear to have presented arguments specifically related to the claim interpretation used by the examiner as forth above in applicant’s most recent response on 10 September 2025. In view of this, the claim interpretation set forth above is understood to be applicable.
Note Regarding IL-12
As best understood by the examiner, human IL-12 (i.e. interleukin 12) would have been understood to have inherently had a molecular weight of 75 kDa, being made from a 35 kDa subunit and a 40 kDa subunit. See Correia et al. (US 2010/0172862 A1), paragraph 0003.
Additionally, the examiner understands that the isoelectric point of human IL-12 to be between about 5 and 6. The reason for this low isoelectric point is because the protein comprises 67 acidic amino acids (which have a negative charge at neutral pH) but only 58 basic amino acids (which have a positive charge at neutral pH). This determination was made in view of the Protpi calculator, available at https://www.protpi.ch/Calculator/ProteinTool#Results and accessed on 3 November 2025. The examiner entered the amino acid sequence of IL-12 into the above-indicated calculator, including to the A and B subunit, and found an isoelectric point 5-6, which is well below 8.
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 1, 3-18, and 30-32 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 1 has been amended to require a water-soluble synthetic polymer. This appears to be new matter which does not appear to be adequately supported by the original application as filed. The examiner notes that the original application as filed does not appear to disclose the phrase “water-soluble synthetic polymer.”
This rejection does not apply to claim 33. This is because claim 33 is drawn to polyvinyl alcohol, which is disclosed by the original application at least as of pages 2-3, paragraph 0012. With that being said, the application’s disclosure of polyvinyl alcohol does not provide adequate support for the subgenus of a water-soluble synthetic polymer. A generic disclosure (e.g. nanospheres) and a specific example (e.g. polyvinyl alcohol) is insufficient to support a subgenus (e.g. a water-soluble synthetic polymer). See MPEP 2163(I)(B).
Claims 31-32 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 31 requires that the therapeutic protein have a particular molecular weight range. This does not appear to be adequately supported by the original application as filed. The only disclosure of a molecular weight range for the therapeutic protein appears to be a range of 5 kDa to 20 kDa on page 2, paragraph 0010 of the instant specification. This does not provide adequate support to new claim 31.
Claim 32 requires an isoelectric point range. The original application as filed does not appear to adequately support this because the original application as filed does not appear to disclose the concept of the isoelectric point.
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, 13-15, 17-18, and 30 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 used for drug encapsulation.
As to claim 1 part (i), the claim requires a PLGA nanosphere. Iqbal teaches the following embodiments as of page 176, Table 2, reproduced below.
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The above-indicated embodiments all contain PLGA and are nanospheres.
As to claim 1, part (ii), the claim requires a water-soluble protein therapeutic substances. Iqbal teaches therapeutic substances above, including protein active agents such as interferon alpha and tetanus toxoid. Iqbal also teaches multiple embodiments in which the therapeutic agent is a protein, such as interferon alpha, egg white lysozyme, and tetanus toxoid on page 176, Table 2, and leuprolide, BDNF, VEGF and others on page 181, Table 4 of Iqbal. These are understood by the examiner to be water-soluble therapeutic proteins.
As to claim 1, part (iii) and (iv), the claims require an oil-soluble surfactant and a water-soluble surfactant. Iqbal teaches the following on page 175, right column, top paragraph, reproduced below.
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As best understood by the examiner, the lipophilic emulsifier is understood to read on the required oil-soluble surfactant and the hydrophilic emulsifier is understood to read on the required water-soluble surfactant.
As to claim 1, part (v), the claim requires a water-soluble synthetic polymer. Iqbal teaches polyvinyl alcohol as of various examples on page 176. This is understood to read on the required water-soluble polymer.
As to claim 1, part (vi), the claim requires albumin. Iqbal teaches the following on page 182, right column, section 4.2.3, relevant text reproduced below.
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As such, the skilled artisan would have been motivated to have used albumin in the formation of the primary emulsion. Iqbal teaches types of albumin such as bovine serum albumin (BSA) on page 176, text reproduced above. While the BSA on page 176 of Iqbal is used for a different purpose than the albumin of page 182, right column, section 4.2.3 of Iqbal, it is nevertheless, the case that the skilled artisan would have recognized BSA as a type of albumin and would have been motivated to have used BSA for the purposes indicated by Iqbal, page 182, right column, section 4.2.3 in order to have predictably stabilized the active ingredient with a reasonable expectation of success.
As to claim 1, 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 claims 13-14, Iqbal teaches PLGA 50:50 as of page 179, right column, section 4.1.2.
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, the bovine serum albumin (i.e. BSA) of Iqbal is understood to read on the required species-specific native serum albumin.
As to claim 18, the nanoparticles of Iqbal appear to be in an aqueous environment. The water of the aqueous environment is understood to read on the required excipient.
As to claim 30, the nanoparticles of Iqbal are present in water; this is understood to read on the required pharmaceutically acceptable excipient.
Claim(s) 3-7 and 31-32 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.
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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 31-32, the skilled artisan would have understood human IL-12, such as that taught or suggested by Zeng, to have inherently had a molecular weight of about 75 kDa and an isoelectric point between 5 and 6. See the section above entitled “Note Regarding IL-12.”
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 31-32 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 claims 31-32, the skilled artisan would have understood human IL-12, such as that taught or suggested by Fahmy, to have inherently had a molecular weight of about 75 kDa and an isoelectric point between 5 and 6. See the section above entitled “Note Regarding IL-12.”
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.
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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.
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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.
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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) 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.
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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.
Response to Arguments Regarding Obviousness Rejections
Applicant has presented arguments regarding the previously applied obviousness rejections, as of applicant’s response mailed on 10 September 2025 (hereafter referred to as applicant’s response). These arguments are insufficient to overcome the applied rejection for the following reasons.
In applicant’s response, applicant argues that the claimed particles demonstrate unexpected, superior properties, as of page 5 of applicant’s response. The examiner does not dispute this position. In fact, the unexpected and superior properties of the instant invention were the basis of the examiner’s decision to allow the claims of parent application 17/830,615. With that being said, it is the examiner’s position that the unexpected results presented by applicant are not commensurate in scope with the claimed invention. The examiner presents the following arguments in support of this position.
Part 1 – The Examiner Has Reiterated Positions from Notice of Allowance of Application 17/830,615 Supporting Unexpected Results: Data in the instant specification indicates that the presence of serum inside the particle would appear to result in improved release and delivery of the IL-12 active agent, as of figure 14 of the instant application, which is reproduced below.
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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.
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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.
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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 IL-12 as the active agent, the sorbitan fatty acid ester having been used as an emulsifier in the inner emulsion, and both polyvinyl alcohol (PVA) AND the polyoxyethylene sorbitan fatty acid ester having been used as the emulsifiers in the outer emulsion. As such, applicant has succeeded in comparing the claimed invention to the closest prior art. See MPEP 716.02(e).
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.
Part 2 – Applicant’s Data is Not Commensurate in Scope With Claim 1: Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. See MPEP 716.02(d).
In this case, the data presented by applicant does not appear to be commensurate in scope with the claimed range. This is because of the following reasons:
The successful example in the instant application comprises polyvinyl alcohol, which would appear to act as a surface stabilizer. In contrast, instant claim 1 is drawn more broadly to a water-soluble synthetic polymer. There would have been no expectation that the desired results could have been achieved in the absence of polyvinyl alcohol. This would likely be the case because polyvinyl alcohol would appear to be useful to prevent particle aggregation by acting as a surface stabilizer, and the skilled artisan would not have expected this result to have occurred in the absence of polyvinyl alcohol.
As such, the results presented by applicant are not commensurate in scope with the instant claims. In view of this lack of commensurateness in scope, the previously applied obvious rejection has been maintained.
Part 3 - Encapsulation Efficiency: Applicant also discusses alleged improved encapsulation efficiency, as of applicant’s response, page 5, bottom paragraph. As best understood by the examiner, encapsulation efficiency is a feature of the method of making the nanoparticle composition rather than the nanoparticle composition itself. As such, even if, purely en arguendo, applicant was to present results showing improved encapsulation efficiency, there does not appear to be a nexus between improved encapsulation efficiency and the claimed composition. See MPEP 716.01(b).
Part 4 - Dependent Claims: Regarding dependent claims, applicant argues that these claims should be allowable for essentially the same reason that the independent claim is allowable, as of pages 6-9 of applicant’s response. No arguments specific to the dependent claims have been set forth. As such, the rejections of the dependent claims have been maintained for essentially the same reason that the rejections of the independent claims have been maintained.
Claim 33 – No Obviousness Rejection
Claim 33 is not subject to an obviousness rejection. This is because the results provided by applicant are understood to be commensurate in scope with the subject matter recited by claim 33. Claim 33 limits the water-soluble synthetic polymer to be polyvinyl alcohol. Applicant has obtained unexpected beneficial results for the recited composition wherein the water-soluble synthetic polymer is polyvinyl alcohol. See the section above entitled “Response to Arguments Regarding Obviousness Rejections”, specifically the subsection entitled “Part 2 – Applicant’s Data is Not Commensurate in Scope With Claims.” In this section of the office action, the examiner took the position that claim 1 is not commensurate in scope with the unexpected results because it is drawn to a broad scope of water-soluble synthetic polymer. However, as claim 33 limits the water-soluble synthetic polymer to polyvinyl alcohol, it is commensurate in scope with the unexpected results.
Claim 33 is not allowable as it is still rejected on the grounds of non-statutory double patenting.
Additional Relevant Prior Art
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 oil soluble and water-soluble 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.
Also as additional relevant prior art that has not previously been cited in the file record but was cited on the information disclosure statement (IDS) submitted on 20 March 2025, the examiner cites Sung et al. (US 2007/0026005 A1). Sung et al. (hereafter referred to as Sung) is drawn to a microsphere comprising IL-12, as of Sung, title and abstract. Sung teaches the following, as of page 6, Example 1, reproduced below.
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Sung differs from the claimed invention in the following manner. The above-composition of Sung, while teaching Pluronic L121 as a first surfactant, does not teach a second surfactant. This is because the polyvinyl alcohol, which is taught by Sung in the above-reproduced, is not understood to be a surfactant; see the above section entitled “Claim Interpretation.” While Sung refers to polyvinyl alcohol as a surfactant in paragraph 0083 of Sung, it actually appears to be the case that the term “surfactant” has a different definition in the instant application as compared with its definition in Sung. Therefore, Sung does not teach all of an oil soluble surfactant, a water-soluble surfactant, and a water-soluble synthetic polymer.
The examiner also takes the following position regarding the Sung reference:
The skilled artisan may not have been motivated to have modified a primary prior art reference with an additional element or method step if that additional element or method step would appear to be extra work and greater expense for no apparent reason. See MPEP 2143(I)(A), Example 3 therein, citing In re Omeprazole Patent Litigation, 536 F.3d 1361, 87 USPQ2d 1865 (Fed. Cir. 2008). In this case, Sung appears to have successfully formed a PLGA particle via double emulsion using only the oil-soluble surfactant (the poloxamer known by the trade name “Pluronic L121”), the water-soluble synthetic polymer polyvinyl alcohol, and bovine serum albumin. Adding a water-soluble surfactant in addition to these ingredients would appear to be additional work and/or greater expense for no apparent benefit, especially since the PLGA double emulsion particle was successfully formed without the water-soluble surfactant.
Nevertheless, applicant has conducted testing showing that addition of a water-soluble surfactant in addition to the ingredients in the above-indicated example results in a particle with superior properties and would solve the problem of poor release. This is explained in the discussion above as well as in applicant’s arguments. This would support the idea that the instant claims are non-obvious over Sung in view of the comparative testing presented in the instant application.
Non-Statutory Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3-18 and 30-33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of copending Application No. 18/946,447 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons:
The instant claims are drawn to a nanoparticle comprising PLGA, a therapeutic substance, a first and second surfactant, and albumin.
The copending claims are drawn to a method of encapsulating a therapeutic substance into a PLGA nanosphere.
The instant and copending claims differ because the copending claims are drawn to a method, whereas the instant claims are drawn to a product. Nevertheless, the resultant product produced by the method of the copending claims would have comprised PLGA, a protein therapeutic substance, an albumin or serum, a first surfactant, and a second surfactant. This product would have been within the claim scope, and would therefore have effectively anticipated the claimed invention, resulting in a prima facie case of anticipatory-type non-statutory double patenting.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
This rejection is not prohibited based upon the third sentence of 35 U.S.C. 121 because the instant application is not a divisional of copending application 18/946,447. See MPEP 804.01 for more information about this issue.
Response to Arguments Regarding Double Patenting Rejection
In applicant’s response on 20 March 2025 (hereafter referred to as applicant’s response), page 9, applicant argues that the applied double patenting rejection should be withdrawn because the instant claims are drawn to a nanosphere whereas the claims of the copending application are method claims. This is not persuasive. The resultant product produced by the method of the copending claims would have comprised PLGA, a protein therapeutic substance, an albumin or serum, a first surfactant, and a second surfactant. This product would have been within the claim scope, and would therefore have effectively anticipated the claimed invention, resulting in a prima facie case of anticipatory-type non-statutory double patenting.
Terminal Disclaimer
The terminal disclaimer filed on 20 March 2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of US Patent 12,214,046 (formerly US application 17/830,615) has been reviewed and is accepted. The terminal disclaimer has been recorded.
Conclusion
No claim is allowed.
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ISAAC . SHOMER
Primary Examiner
Art Unit 1612
/ISAAC SHOMER/ Primary Examiner, Art Unit 1612