Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
Receipt is acknowledged of Applicants’ amendment and remarks, filed on 03/03/2026, in which claims 35, 41, and 43-47 are amended and claims 1-34, 36-38, 40, and 48-54 are canceled.
Claims 35, 39, and 41-47 are pending and are examined on the merits herein.
Priority
The instant application is a 371 of PCT/IL2020/051248, filed on 12/03/2020, which claims domestic benefit to 62/943,824, filed on 12/05/2019.
Objections and Rejections Withdrawn
Applicant’s amendment and remarks, filed 03/03/2026, with respect drawings are objected to because a portion of the axis label in figure 11A is missing has been fully considered and is persuasive, as replacement drawings have been submitted. This objection has been withdrawn.
Applicant’s amendment and remarks, filed 03/03/2026, with respect that claims 38 and 43-46 are rejected under 35 U.S.C. 112(b) has been fully considered and is persuasive, as claim 38 is canceled and claims 43-46 have been amended to correct dependency and provide antecedent basis. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 03/03/2026, with respect that claims 35, 41-42, and 45 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhang has been fully considered and is persuasive, as the scope of claim 35 has been amended to limit chemically modified starch by crosslinking with divanillin. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 03/03/2026, with respect that claims 35 and 39-40 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Thyriyalakshmi has been fully considered and is persuasive, as the scope of claim 35 has been amended to limit chemically modified starch by crosslinking with divanillin. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 03/03/2026, with respect that claims 36-38 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Saikia in view of Gaur as evidenced by PubChem has been fully considered and is persuasive, as claims 36-38 and 40 are canceled. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 03/03/2026, with respect that claim 46 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang in view of Zhao has been fully considered and is persuasive, as the scope of claim 35 has been amended to limit chemically modified starch by crosslinking with divanillin. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 03/03/2026, with respect that claims 35-37 and 39-41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 35-43 of copending Application No. 17/829,302 has been fully considered and is persuasive, as a terminal disclaimer has been approved for copending Application No. 17/829,302. This rejection has been withdrawn.
The following are maintained or new grounds of rejection necessitated by Applicant’s amendment, in which the base claim 35 is amended to incorporate the new combination of limitations requiring chemically modified starch by crosslinking with divanillin, provided in the form of nano-sized particles.
Drawings
The replacement drawings are objected to because they introduce the new issue of the signal labels is figure 11B are now illegible. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 35, 39, 41-43, and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Saikia et al. (International Journal of Biological Macromolecules, 2016; PTO-892 09/03/2025) further in view of Gaur et al. (Bull. Korean Chem. Soc. 2009; PTO-892 09/03/2025) and as evidenced by PubChem in PTO-892 (Divanillin PubChem CID 95086 09/03/2025).
Saikia discloses the synthesis of curcumin loaded aminated starch coated iron oxide magnetic nanoparticles (abstract). The instant specification defines curcumin as a CNS-active drug (Specification [009]). Saikia teaches that different chemicals have been explored to crosslink polymer chains and compares the effects of different crosslinking agents on release characteristics of curcumin from the nanoparticles. Saikia compares use of glutaraldehyde, genipin, and citric acid as crosslinkers (page 1122, paragraph 1). Saikia teaches that genipin did not show toxicity to cells due to its natural origin, making it a good candidate for chemotherapy (page 1129, paragraph 1). Saikia teaches that crosslinking can highly influence the encapsulation efficiency and swelling behavior of the polymer matrix and thus significantly influence the release of the incorporated drug from the polymer matrix (paragraph bridging pages 1121-1122). Encapsulation efficiency and loading efficiency of curcumin depended on the identity of the crosslinker (Table 1). Crosslinking can also control the size of the polymer matrix and thus the size of the nanoparticles, which is important in determining the magnetic properties of the nanoparticles (paragraph bridging pages 1121-1122). Saikia demonstrates that the size of the crosslinked nanoparticle depended on the identity of the crosslinker, with a strong covalent bond forming between polymer and glutaraldehyde crosslinker and resulting in a more compact nanoparticle as compared to a less compact nanoparticle forming when the polymer is crosslinked with weak bonds by citric acid as a linker (page 1124, paragraph 1). Saikia teaches that the development of safe and biocompatible drug delivery systems having controlled release therapeutic properties is essential for cancer treatment (page 1131, paragraph 3). Saikia discloses the nanoparticles dissolved in a mixture of water and ethanol (page 1122, paragraph 5).
Although Saikia teaches nanoparticles comprising chemically modified crosslinked starch, the teachings of Saikia differ from that of the instantly claimed invention in that Saikia does not teach divanillin as the crosslinker (instant claim 35).
Gaur provides a structural characterization of dehydrodivanillin which is a natural product isolated from plant species. It is commercially important in the cosmetics, pharmaceuticals and food stuffs industries as an antioxidant and a flavoring agent (page 2895, paragraph 1). Gaur shows the structure of dehydrodivanillin, which is a dialdehyde (Figure 1). Gaur teaches that dehydrodivanillin has potential to be used for crosslinking polymers (page 2898, paragraph 1). The instant specification defines divanillin as 3-(5-formyl-2-hydroxy-3-methoxyphenyl)-4-hydroxy-5-methoxybenzaldehyde, having a CAS number 2092-49-1 (Specification [0029]). As evidenced by PubChem CID 95086 divanillin has the CAS number 2092-49-1 and is also known as dehydrodivanillin.
It would have been prima facie obvious to combine the teachings of Saikia and Gaur before the effective filing date of the claimed invention by substituting the dehydrodivanillin of Gaur as a crosslinker in the starch polymer matrix of the curcumin loaded nanoparticles of Saikia to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to modify the nanoparticles of Saikia with the dehydrodivanillin of Gaur because Saikia teaches that the identity of the crosslinker is a result effective variable for the size and encapsulation efficiency of the nanoparticles and Gaur teaches that dehydrodivanillin may be used for crosslinking polymers. One of ordinary skill in the art would have a reasonable expectation of success because Saikia teaches that the nanoparticles may be crosslinked with glutaraldehyde, which is a small molecule dialdehyde, and Gaur teaches that dehydrodivanillin, which is also a small molecule dialdehyde, may be used for crosslinking polymers. Furthermore, one of ordinary skill in the art would have been motivated to substitute the dehydrodivanillin as a crosslinker for the nanoparticles of Saikia because Saikia teaches that the development of safe and biocompatible drug delivery systems having controlled release therapeutic properties is essential for cancer treatment and that crosslinkers with a natural origin and no toxicity to cells are a good candidate for chemotherapy. Gaur teaches that dehydrodivanillin is a natural product isolated from plants and is used as a cosmetic and a flavoring agent, with suggests that it is not toxic.
Claim 44 is rejected under 35 U.S.C. 103 as being unpatentable over Saikia et al. (International Journal of Biological Macromolecules, 2016; PTO-892 09/03/2025) further in view of Gaur et al. (Bull. Korean Chem. Soc. 2009; PTO-892 09/03/2025) and as evidenced by PubChem in PTO-892 (Divanillin PubChem CID 95086 09/03/2025) as applied to claim 35 above, further in view of Navari et al. (N Engl J Med, 2016; PTO-892 09/03/2025)
The combined teachings of Saikia and Gaur are as above.
The combined teachings of Saikia and Gaur differ from that of the instantly claimed invention in that they do not teach a composition comprising an antiemetic (instant claim 44).
Navari discusses the state of the art in antiemetic prophylaxis for chemotherapy-induced emesis which is chemotherapy-induced nausea and vomiting. Navari teaches that emesis is a common treatment-related side effect having a detrimental effect on the quality of life of patients with cancer and may lead to dose reductions in or discontinuation of chemotherapy. Adherence to antiemetic guidelines provides effective relief from chemotherapy-induced emesis (abstract). Navari teaches that prophylaxis should be the primary goal of antiemetic therapy (page 1362, paragraph 3). Navari teaches that even for chemotherapy with a low emetic risk, guidelines suggest an antiemetic drug be provided with treatment (paragraph bridging pages 1362-1363). Navari teaches a variety of antiemetic drugs, including metoclopramide and dexamethasone (page 1360, paragraph 1) and olanzapine (paragraph bridging pages 1361-1362).
It would have been prima facie obvious to combine the teachings of Saikia, Gaur, and Navari before the effective filing date of the claimed invention by including an antiemetic drug as taught by Navari in the anti-cancer composition suggested by the combined teachings of Saikia and Gaur to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to modify the hydrogel suggested by the combined teachings of Saikia and Gaur by incorporating an antiemetic drug because Saikia teaches that the development of safe and biocompatible drug delivery systems having controlled release therapeutic properties is essential for cancer treatment. One of ordinary skill in the art would have a reasonable expectation of success because Saikia teaches a composition for the treatment of cancer and demonstrates that the crosslinked hyaluronic acid hydrogel is capable of incorporating small molecules and Navari teaches that an antiemetic drug should be provided with treatment even for chemotherapy with a low emetic risk and teaches small molecule antiemetics, such as metoclopramide, dexamethasone, and olanzapine.
Claims 35, 39, 41-42, 45, and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Alsayed et al. (US 2024/0101721 A1, 2024; PTO-892).
Alsayed discloses hydrophobically-modified polysaccharides and their use in microencapsulation (abstract). Alsayed teaches that microencapsulation is used for products in the pharmaceutical industry, cosmetics, household and personal care, food, agriculture, chemistry, and biotechnology, among others [0003], but that synthetic polymers pose a health hazard because they are toxic and non-biodegradable [0004]. Alsayed teaches microencapsulation that is environmentally-friendly and safe [0005].
Alsayed teaches microcapsules that are formed by mixing a hydrophobically-modified polysaccharide and a water-insoluble material [0010]. One method of making the microcapsules includes dispersing the hydrophobically-modified polysaccharide in an aqueous medium and subsequently adding the water-insoluble material [0060]. Aqueous medium is defined as comprising water and may also comprise one or more organic solvents that are miscible in water [0061].
Examples of suitable polysaccharides include, among others, starch [0048]. The emulsion may be further reacted with a crosslinker to crosslink the hydrophobically-modified polysaccharide in order to further stabilize the emulsion. Suitable crosslinkers include, among others, phenolic dialdehydes such as terephthalaldehyde or di-vanillin [0067]. The water-insoluble material may be an active material, including, among others, an antibacterial agent, anesthetic, analgesic, enzymes and co-enzymes, or chemotherapeutic agents [0062].
The size of the microcapsules made by reacting the emulsion with a crosslinker may be determined by dynamic light scattering using standard instrumentation such as a Zetasizer instrument. Alsayed teaches that the microcapsule size is from 100 nm to 200 μm, typically from 200 nm to 100 μm, and more typically from 300 nm to 30 μm [0075]. Alsayed provides examples of the microcapsules analyzed by Zetasizer analysis and shows that they are 520 nm (Table 3, [0093]). The instant specification defines nanoparticle nano-sized as any nano-sized particles and states that the particle has a particle size in the range of nanometers, e.g. between 10 and 950 nm (instant specification [0036]).
Although Alsayed separately teaches a modified starch and a divanillin crosslinker as suitable for the formation of microcapsules, the teachings of Alsayed differ from that of the instantly claimed invention in that Alsayed does not provide an example of a modified starch crosslinked with divanillin (instant claim 35).
One of ordinary skill in the art would have been motivated to crosslink the microcapsules comprising a starch polysaccharide taught by Alsayed using divanillin in order to achieve the predictable result of a non-toxic microcapsule because Alsayed teaches that crosslinking the hydrophobically-modified polysaccharide further stabilizes the composition. One of ordinary skill in the art would have a reasonable expectation of success in using divanillin to crosslink the microcapsules of Alsayed because Alsayed teaches that phenolic dialdehydes including divanillin are suitable crosslinkers.
Claim 46 is rejected under 35 U.S.C. 103 as being unpatentable over Alsayed et al. (US 2024/0101721 A1, 2024; PTO-892) as applied to claim 35 above, further in view of Singnurkar et al. (Indian Journal of Pharmaceutical Sciences, 2008; PTO-892).
The teachings of Alsayed are as above. Alsayed additionally teaches that the active material may be a pharmaceutic [0063].
The teachings of Alsayed differ from that of the instantly claimed invention in that they do not teach a composition comprising insulin (instant claim 46).
Singnurkar teaches that oral delivery formulations for insulin are highly desirable from a patient compliance point of view. However, only a small portion of insulin administered orally reaches the blood stream mainly due to extensive degradation of the protein in the gastrointestinal tract (page 721, paragraph 1). A drug carrier for insulin should provide a stable and biocompatible environment (paragraph bridging page 721-722). Singnurkar discloses insulin loaded hydrophobic nanoparticles (abstract), and teaches that they retain the biological activity of insulin and improve the oral absorption of insulin (page 726, paragraph 1). Singnurkar teaches that the nanoparticles are prepared using a solution containing insulin, HP-β-CD, and zinc chloride (page 722, paragraph 2) . Singnurkar suggests that the nanoparticles are formed with an insulin-zinc-HP-β-CD interaction (page 724, paragraph 5).
One of ordinary skill in the art would have been motivated to select insulin as the active material in the microcapsules of Alsayed because Singnurkar teaches that the formulation of insulin in nanoparticles improves oral absorption and that an oral delivery formulation for insulin is highly desirable. One of ordinary skill in the art would have had a reasonable expectation of success because Singnurkar teaches that insulin is a suitable hydrophobic active compound to be included in nanoparticles and Alsayed teaches that the active material may be a pharmaceutic.
Response to Arguments
Applicant's arguments filed 03/03/2026 have been fully considered but they are not persuasive.
Insofar as Applicant’s arguments are applicable to the current rejections, Applicant argues that the current obviousness rationale is an obvious to try rationale and must therefore demonstrate that dehydrodivanillin itself is an identified predictable solution for crosslinking (remarks, page 7, paraph 4). This is not persuasive.
The current obviousness rationale is based on KSR rationale (G) from MPEP 2141(III). According to the current obviousness rejection, one of ordinary skill in the art would have been motivated to modify the crosslinked nanoparticles of Saikia with the dehydrodivanillin of Gaur because Saikia teaches that crosslinkers with a natural origin and no toxicity to cells are a good candidate for chemotherapy and the teachings of Guar suggest that dehydrodivanillin is a non-toxic natural product that is useful in the crosslinking of polymers.
Applicant further argues that Gaur does not teach that dehydrodivanillin is useful for crosslinking polymers (remarks, page 8, paragraph 4) and that Saikia provides no guidance about what other crosslinker molecules might exhibit desirable characteristics (remarks, page 8, paragraph 2). This is not persuasive.
Gaur's statement "dehydrodivanillin has shown immense potential to be used for the development of conducting polymers and crosslinkers for polymers" at page 2898, paragraph 1 clearly teaches and suggests that dehydrodivanillin be used as a crosslinker for polymers. One of ordinary skill in the art would not require express embodiment of dehydrodivanillin as a crosslinker because Saikia identifies which characteristics of crosslinkers impact the resulting nanoparticle, specifically the strength of bond forming between polymer and crosslinker, such that one of ordinary skill in the art would understand that the identity of the crosslinker is a result effective variable for the size and encapsulation efficiency of the nanoparticles. Saikia additionally provides examples such that one of ordinary skill in the art would have understood that dialdehydes are suitable as crosslinkers.
Applicant further disagrees with the statement of reasonable expectation of success provided in the obviousness rationale, arguing against the similarity of dehydrodivanillin and glutaraldehyde. Applicant argues that the molar masses of glutaraldehyde and divanillin are so dissimilar that one of ordinary skill in the art would have not considered substituting the divanillin of Gaur for the glutaraldehyde of Saikia (remarks, page 9, paragraph 4). This is not persuasive.
The statement of reasonable expectation of success indicates that dehydrodivanillin and glutaraldehyde would both have been understood by one of ordinary skill in the art as organic compounds that bear the same dialdehyde functional groups. Applicant does not provide any rationale of why the difference in molecular weight between the dialdehyde of Gaur and the glutaraldehyde of Saikia is such that one of ordinary skill in the art would have considered the dialdehyde of Gaur to be a small organic molecule.
Because Applicant’s arguments are not persuasive, the instant claims are rejected for the reasons of record with modifications made to account for the claim amendments filed 03/03/2026.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
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/S.G.H./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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