DETAILED ACTION
Applicants’ arguments, filed 18 August 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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.
Foreign Priority
In the prior office action, the examiner stated the following:
Previously in the prosecution history, the examiner took the position that foreign priority application SG10202007118P does not appear to adequately support the claimed subject matter. In response, applicant provided an interim copy of the foreign priority documents on 31 October 2025, and provided arguments regarding this issue on page 8 of applicant’s response on 31 October 2025.
In response, the examiner takes the position that in the case of foreign priority, the foreign application must be for the same invention as the application in the United States. See MPEP 213, item (D). In this case, both the certified and the interim copies of the foreign priority document do not appear to be drawn to the same invention as that in the instant application at least because the order of the pages in the foreign priority documents differ from the order of the pages in the instant application.
As such, applicant’s arguments regarding the foreign priority documents are not persuasive.
Applicant does not appear to have addressed this issue in applicant’s response on 23 March 2026.
In response, applicant takes the following position in applicant’s response on 18 August 2026, pages 8-9, wherein part of applicant’s response has been reproduced below.
PNG
media_image1.png
404
634
media_image1.png
Greyscale
The examiner does not dispute this argument with respect to an interim copy of the foreign priority document. As such, the previously applied objection has been withdrawn.
Claim 21 – Withdrawn 112(b) Rejection, Claim Interpretation, Cited Prior Art
Claim 21 and claims dependent thereon were previously rejected for indefiniteness for the following reasons.
Claim 21 recites that the positively charged drug layer may comprise insulin. It is unclear how this claim limitation further limits the claimed subject matter. This is because the skilled artisan would have expected insulin to have been negatively charged at neutral pH… As such, it is unclear whether insulin is in the scope of claim 21 because the skilled artisan would not have expected insulin to have formed a positively charged layer.
In response, applicant amended claim 21 to require that the drug is present in the positively charged layer in a positively charged state. Although the word “state” does not appear in the original disclosure, this term is understood to be adequately supported in view of the instant specification on page 17, paragraph 0087, which discloses the following, wherein specific text from paragraph 0087 is reproduced below.
PNG
media_image2.png
84
628
media_image2.png
Greyscale
This is understood to support the requirement that the drug is present in the positively charged layer in a positively charged state.
A search conducted by the examiner indicates that natural insulin has an isoelectric point of about pH 5.3 to 5.4. However, other forms of insulin have a different isoelectric point. For example, insulin glargine has an isoelectric point of about pH 7; see Salnikova et al. (US 2017/0340738 A1), paragraph 0048. Additionally, Watson et al. (US 2017/0174737 A1) discloses insulins and insulin analogs or derivatives having an isoelectric point of 4.5 to 8.5, as of paragraph 0058 of Watson. As best understood by the examiner, it is the insulin analogs with higher isoelectric points that would be most amenable to being formulated in the manner recited by claim 21 (in the case wherein the positively charged is an insulin or derivative/analog thereof). This is because these insulins, insulin analogs, or insulin derivatives are most likely to be positively charged as there is a greater pH range at which said insulin derivatives can be positively charged.
As relevant prior art regarding claim 21, the examiner cites Zhang (“Studies of Insulin Transport Across Intestinal Epithelium Using Nano-Encapsulation for Oral Delivery” Thesis, Nanyang Technological University Singapore, 2018, pages i-xxi, 1-165, and various introductory pages). Zhang is drawn to liposomes and insulin delivery, as of Zhang, pages ii-iii, title and abstract. Zhang provides an example of a liposome comprising multiple layers of insulin and chitosan on page 142, figure 41(a), reproduced below.
PNG
media_image3.png
310
802
media_image3.png
Greyscale
Also see Zhang, page 148, relevant table reproduced below.
PNG
media_image4.png
322
834
media_image4.png
Greyscale
The above-indicated liposome has five alternating layers of chitosan and insulin surrounding the liposome. Chitosan forms the positively charged layer because chitosan is a polymer containing amine groups which are protonated under neutral conditions. Insulin is the negatively charged layer.
As such, Zhang teaches insulin as the negatively charged layer. Zhang does not teach formulating a composition wherein insulin is positively charged. Zhang also does not teach delivering a protein other than insulin which is positively charged. For this reason, instant claim 21 is not anticipated by Zhang or obvious over Zhang.
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, 4-5, 7, and 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (“Studies of Insulin Transport Across Intestinal Epithelium Using Nano-Encapsulation for Oral Delivery” Thesis, Nanyang Technological University Singapore, 2018, pages i-xxi, 1-165, and various introductory pages).
Zhang is drawn to liposomes and insulin delivery, as of Zhang, pages ii-iii, title and abstract. Zhang provides an example of a liposome comprising multiple layers of insulin and chitosan on page 142, figure 41(a), reproduced below.
PNG
media_image3.png
310
802
media_image3.png
Greyscale
Also see Zhang, page 148, relevant table reproduced below.
PNG
media_image4.png
322
834
media_image4.png
Greyscale
The above-indicated liposome has five alternating layers of chitosan and insulin surrounding the liposome. The outer layer is chitosan, which is positively charged. The active agent is insulin.
As to claim 1, the claim requires a drug load of at least 10%. Zhang appears to teach a drug load of at maximum between about 1% and 1.5%, as of Zhang, page 150, figure 45, relevant portion of figure reproduced below.
PNG
media_image5.png
254
804
media_image5.png
Greyscale
As such, Zhang fails to anticipate instant claim 1 for at least this reason.
Nevertheless, the teachings of Zhang in the above-reproduced figures indicate that an increase in the number of layers results in an increase of the loading percentage. As such, the skilled artisan would have been motivated to have optimized the number of layers in order to have increased the amount of active agent loaded in order to have reached the claimed requirement of at least 10 wt% loading. Optimization requires a reasonable expectation of success; see MPEP 2144.05(II)(B). In this case, the data in Zhang would appear to indicate that there would have been a reasonable expectation that increasing the number of layers would have resulted in an increase in the amount of active agent loaded. Additionally, the table at the top of page 148 of Zhang is understood by the examiner to provide motivation for the skilled artisan to have modified Zhang by optimizing the number of layers.
As to claim 1, the claim requires eleven coating layers. Zhang does not appear to teach this many coating layers. Nevertheless, addition of additional coating layers would appear to be an issue of routine optimization. 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, Zhang teaches the general conditions of a liposome coated with multiple alternating layers of chitosan and insulin, and suggests optimizing the number of layers, as of Zhang, multiple locations in the reference including page 148, table at top of page. As such, it would not have been inventive for the skilled artisan to have added more layers than what was exemplified by Zhang by routine experimentation.
As to claim 1, the claim requires a particle size of 500 nm or less. This appears to be taught by Zhang, as the particle sizes of Zhang appear to be in the range of about 101-170 nm. Zhang appears to teach about 10-20 nm increase in diameter per layer. As Zhang achieved about 170 nm for a five layer particle, the skilled artisan would have expected that a 20 nm particle would have had 6 additional layers. As such, addition of 6 layers of 20 nm onto the 170 nm five layer particle would have resulted in a particle sized about 290 nm, which is still well below the required maximum of 500 nm.
As to claim 4, the claim requires hydrogenated soy phosphatidylcholine (HSPC) and dipalmitoyl phosphatidylglycerol (DPPG) in a certain ratio. Zhang teaches a liposome made from DPPG and HSPC. Zhang appears to be silent regarding the ratio at which these components are mixed. 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, Zhang teaches the general conditions of a HSPC/DPPG liposome. As such, it would not have been inventive for the skilled artisan have discovered the optimum or workable ranges of the ratio of HSPC to DPPG via routine experimentation.
As to claim 5, the outer layer of the above-indicated liposome comprises chitosan.
As to claim 7, Zhang appears to suggest insulin in the liposome core, as of page 120, bottom paragraph.
As to claim 10, Zhang teaches Eudragit S100 coating on page 150, section 6.3.4. Eudragit S150 is the trade name of a polymethacrylate polymer modified with carboxylic acid groups. Eudragit S150 is an enteric coating because it is insoluble at the low pH values found in the stomach but dissolves at higher pH values such as those found in the intestine. Eudragit S100, as of Zhang is the same coating used in the instant specification on page 8, paragraph 0049. As such, the skilled artisan would have expected the Eudragit S100 of Zhang to have had the same properties (e.g. with regard to being low-swelling) as required by the instant claims. Something which is old (e.g. Eudragit S100) does not become patentable upon the discovery of a new property, and this feature need not have been recognized at the time of filing. See MPEP 2112(I & II).
Claim 21 Not Rejected: This rejection does not apply to claim 21 and claims dependent thereon. This is because claims 21 and claims dependent thereon require a negatively charged polymer layer and a positively charged drug layer. Zhang teaches neither of these features. In contrast, Zhang teaches a positively charged polymer layer, which is chitosan, and a negatively charged drug layer, which is insulin.
Response to Arguments
Applicant has presented arguments regarding the previously applied rejection, as of applicant’s response on 18 August 2026 (hereafter referred to as applicant’s response). These arguments are addressed below.
In applicant’s response, page 11, applicant makes the following arguments.
PNG
media_image6.png
144
626
media_image6.png
Greyscale
To the extent that this is an argument that the skilled artisan would have expected the particle of Zhang to have been too large to have met the claimed requirements, this is not persuasive. Zhang teaches a particle size of about 100-102 nm for an uncoated particle and about 164-170 nm for a particle with a coating of five layers. As such, Zhang appears to teach about 10-20 nm increase in diameter per layer. As Zhang achieved about 170 nm for a five layer particle, the skilled artisan would have expected that a 20 nm particle would have had 6 additional layers. As such, addition of 6 layers of 20 nm onto the 170 nm five layer particle would have resulted in a particle sized about 290 nm, which is still well below the required maximum of 500 nm. Therefore, the skilled artisan would have had a reasonable expectation that had the particle of Zhang been modified to have included 11 layers, the resultant particle would still have successfully been sized well below 500 nm.
Applicant’s arguments above also discuss particle size control. It is not clear to the examiner as to exactly what is meant by this term. The examiner notes that particle size control could refer to particle size uniformity or polydispersity index. However, the instant claims do not recite a specific polydispersity index or other measure of particle size uniformity. As such, applicant’s arguments regarding particle size control are not persuasive. The examiner notes that a particle population wherein the particles are non-uniform in size but are sized at 500 nm or less is still understood to meet the claimed requirements.
Applicant then argues that the prior art fails to teach at least 10 wt% drug loading, as of applicant’s response, page 11. The examiner does not dispute this. In the examples of Zhang, it is noted that Zhang teaches a maximum of between about 1-1.5% drug loading. However, the teachings of Zhang clearly indicate a trend of increased loading when additional levels are added. As such, there would have been a reasonable expectation that, had Zhang been modified to have included more layers, the result of such a modification would have been a particle having at least 10 wt% drug loading.
Applicant then argues the following, as of the bottom of page 11, relevant text reproduced below.
PNG
media_image7.png
142
612
media_image7.png
Greyscale
In response, the examiner notes that Zhang teaches the following, as of page 150, figure 45, relevant figure reproduced below.
PNG
media_image5.png
254
804
media_image5.png
Greyscale
The examiner understands from this figure that the increase in loading is modest after layer 2 but becomes more significant after layer 4 – this is most evident as of the figure reproduced above right. As such, the amount of increase in loading appears to increase with every additional two layers added. This appears to indicate that drug load not only increases but accelerates with increasing number of layers. As such, the skilled artisan would have expected the increase in the amount of insulin loaded to have increased quite significantly upon modification of Zhang to have been six layers, then increased even more significantly upon modification of Zhang to have had eight layers, and so on. Therefore, there would have been a reasonable expectation that modifying Zhang to have more layers would have resulted in an increase of the amount of insulin loaded to have achieved the required at least 10 wt%.
Applicant then argues that Zhang provides no teaching that such increases (e.g. increases in the number of insulin layers) can continue indefinitely. This is not persuasive. Applicant has not presented evidence showing why the skilled artisan would not have expected increasing the number of layers of Zhang to have been successful. Obviousness requires a reasonable expectation of success, not absolute predictability. See MPEP 2143.02(II). The examiner notes that applicant may present evidence showing a lack of a reasonable expectation of success; however, the assertion in applicant’s response that increases in the number of layers cannot continue indefinitely does not meet the requirement of presenting such evidence of a lack of a reasonable expectation of success. Argument does not replace evidence where evidence is necessary. See MPEP 2145(I).
Applicant then makes the following argument on page 12, relevant text reproduced below.
PNG
media_image8.png
82
634
media_image8.png
Greyscale
Regarding the issue of size, the examiner agrees that increasing the number of layers increases particle size. However, based upon the teachings of Zhang, the skilled artisan would not have expected that increasing particle size from 5 layers to 11 layers to have resulted in the particles being larger than 500 nm.
Regarding the issue of stability and zeta potential, the examiner notes that Zhang has provided extensive stability testing. However, the examiner was unable to locate in Zhang a teaching that would have caused the skilled artisan to have expected that increasing the number of layers of the particle of Zhang would have resulted in an unstable particle. Furthermore, although Zhang teaches an enteric coating at various parts of the reference, the stability testing conducted by Zhang appears to be drawn to non-enteric coated particles. In contrast, the claimed particles are optionally enteric coated. As the enteric coating affects the outside of the particles, enteric coating would have been expected to have significantly affected particle stability and the skilled artisan would not have expected the data in Zhang to have been applicable to enteric coated particles.
Applicant then makes the following arguments as of page 12, second full paragraph.
PNG
media_image9.png
108
608
media_image9.png
Greyscale
In response, the examiner takes the position that the above-indicated parameters, while beneficial, do not appear to be unexpected based upon the teaching of Zhang. Regarding the particle size, this is because the particle size increase per increasing layer taught by Zhang appears to be small enough that the skilled artisan would have expected an 11-layer particle to have been below 500 nm in size. Regarding the amount of drug, it is noted that Zhang teaches that the increase in insulin content increases with each additional set of two layers. As such, these properties would have been expected in view of the teachings of Zhang. Expected beneficial results are evidence of obviousness. See MPEP 716.02(c)(II).
Applicant then argues that claim 1 is not drawn to routine optimization of a known parameter, as of applicant’s response, page 12, bottom paragraph. This is not persuasive. Claim 1 is drawn to optimization of the number of layers. As Zhang teaches multiple different particles with multiple different numbers of layers, the examiner takes the position that optimization of the number of layers would have been routine.
Applicant makes the following argument as of page 13, top half of page, relevant text reproduced below.
PNG
media_image10.png
166
638
media_image10.png
Greyscale
This is not persuasive. That each set of two layers results in significant increases in drug loading that increase with each increasing set of two layers appears evident by Zhang and is not an unexpected property. Also, that increased amount of drug in the dosage form renders increased amounts of drug to be bioavailable appears to be what the skilled artisan would have expected and does not appear to be an unexpected result.
Applicant then cites figure 8 and Example 1K, as of applicant’s response, page 11. Figure 8 is reproduced below.
PNG
media_image11.png
382
598
media_image11.png
Greyscale
Applicant appears to have compared the claimed invention against solutions, rather than nanoparticles with less than the required numbers of layers. In contrast, the closest prior art is drawn to a nanoparticle with less than the required number of layers. As such, figure 8 does not appear to represent a comparison to the closest subject matter to actually exist in the prior art. Such comparisons are not probative of non-obviousness; see MPEP 716.02(e).
Allowable Subject Matter
Claims 21-24 appear to be in condition for allowance.
As relevant prior art, the examiner cites Zhang (“Studies of Insulin Transport Across Intestinal Epithelium Using Nano-Encapsulation for Oral Delivery” Thesis, Nanyang Technological University Singapore, 2018, pages i-xxi, 1-165, and various introductory pages), which is cited above. Zhang is drawn to liposomes and insulin delivery, as of Zhang, pages ii-iii, title and abstract. Zhang provides an example of a liposome comprising multiple layers of insulin and chitosan on page 142, figure 41(a), reproduced below.
PNG
media_image3.png
310
802
media_image3.png
Greyscale
Also see Zhang, page 148, relevant table reproduced below.
PNG
media_image4.png
322
834
media_image4.png
Greyscale
The above-indicated liposome has five alternating layers of chitosan and insulin surrounding the liposome. Chitosan forms the positively charged layer because chitosan is a polymer containing amine groups which are protonated under neutral conditions. Insulin is the negatively charged layer.
As such, Zhang teaches insulin as the negatively charged layer. Zhang does not teach formulating a composition wherein insulin is positively charged. Zhang also does not teach delivering a protein other than insulin which is positively charged. For this reason, instant claim 21 is not anticipated by Zhang or obvious over Zhang.
As no other rejections are applied to claim 21, it is the examiner’s position that claims 21 and claims dependent thereon appear to be in condition for allowance.
Additional Relevant Art
As additional relevant art, the examiner cites Zhang et al. (Nanoscale, Vol. 13, 2021, pages 776-789). This reference appears to be drawn to the same subject matter as recited by the instant claims. Nevertheless, no rejection has been written over this reference for at least the following reasons.
The instant application claims foreign priority to a foreign application filed on 24 July 2020, and is a national phase of a PCT application filed on 23 July 2021.
As an initial matter, Zhang et al. (Nanoscale, Vol. 13, 2021, pages 776-789) was published on 11 November 2020. This is after the date of 24 July 2020.
Even if, purely en arguendo, a filing date of 23 July 2021 is assumed, the instant claims are not rejected over Zhang et al. (Nanoscale, Vol. 13, 2021, pages 776-789). This is because
Zhang et al. (Nanoscale, Vol. 13, 2021, pages 776-789) was published less than a year earlier than the filing date of 23 July 2021;
Zhang et al. (Nanoscale, Vol. 13, 2021, pages 776-789) appears to have the same inventive entity as the instant application;
As such, Zhang et al. (Nanoscale, Vol. 13, 2021, pages 776-789) would not appear to be prior art in view of the exception under AIA 35 U.S.C. 102(b)(1)(A).
As such, no rejection over Zhang et al. (Nanoscale, Vol. 13, 2021, pages 776-789) has been written by the examiner.
Conclusion
Less than all claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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
