DETAILED ACTION
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 .
Election/Restrictions
To summarize the current election, the applicant elected Group I and the species where the claimed active agent, marker, and/or biomolecule are absent.
For the sake of compact prosecution, the species election is expanded to the embodiment with covalently crosslinked glycosylated mucin nanoparticles comprising a compound that is cefuroxime, a cephalosporin, because it was encountered during the prior art search. Claims 5-6 are rejoined to the degree they read on this additional species.
Claims 7-8, 10-15, 23, 25-27, and 31-32 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and species, there being no allowable generic or linking claim.
Claim Rejections - 35 USC § 112
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, 5-6, and 33 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 recites “wherein the surface of the nanoparticles is glycosylated in an amount between 34.0% to 94.1% with respect to the amount present on said mucin before synthesizing said nanoparticles.” Claim 33 recites “wherein the surface of the nanoparticles is glycosylated in an amount between 34.0% to 50% with respect to the amount present on said mucin before synthesizing said nanoparticles.” The disclosure does not detail 34 % and 94.1% as the amount of glycosylation relative to the mucin prior to synthesis of the nanoparticles. The quantification in the specification notes that the nanoparticle surfaces have about half the amount of oligosaccharide on as compared to the starting mucin (see example 5). There is no clear basis for the additional percentages of glycosylation that are now claimed. The applicant’s remarks dated October 25, 2025 referencing the UV-Vis absorbance intensity values of figure 11 do not clearly translate to the ranges of glycosylation that are now claimed. In addition, the applicant seeks to assert that the amount of glycosylation they obtained was an unexpected outcome, thus the unexpected values need to have been contemplated at the time of filing. As a result, the artisan of ordinary skill would not have deemed the applicant to be in possession of the invention as currently claimed.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3, 5-6, and 33 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The declaration filed October 24, 2025 states,
“Six biologically independent experiments were conducted using nanoparticle suspensions at concentrations of 25, 75, 100, and 150 µg/mL. For each concentration, the glycan content of the nanoparticles was compared to that of an equivalent mass of native porcine gastric mucin (PGM) analyzed under identical conditions.”
The results of what appear to be the same nanoparticles assessed at different suspension concentrations are relative amounts of glycosylation present on the nanoparticle surface that changes depending on the concentration of nanoparticles used for assessment (see declaration figure 1). As a result it appears that a single preparation of mucin nanoparticles may be both inside and outside the scope of the claims, depending on the degree of dilution employed during assessment. Alternatively, the declarant’s showing could also imply that the amount of surrounding medium changes the mucin nanoparticles such that the oligosaccharide chains rearrange. Applicable options for such a surrounding medium are not readily evident from the disclosure As a result, the metes and bounds of the claims are unclear.
Claim Rejections - 35 USC § 103
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.
Claims 1-3 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Fukui et al. (previously cited) in view of Hamidi et al. (previously cited) as evidenced by Wirth et al. (previously cited) and Abodinar et al. (International Journal of Biological Macromolecules 2016 87:281-286).
Fukui et al. teach mucin gel nanoparticles that are composed of pig gastric mucin (see abstract, page 783 first column first paragraph and second column first full paragraph). The nanoparticles are crosslinked via hydrophobic interactions and hydrogen bonding due to pH that are facilitated by the temporary presence of an oppositely charged surfactant and are further crosslinked via chain entanglement that is induced due to heat (see page 784 second column first partial paragraph-page 785 second column first partial paragraph). The additional crosslinking provided added stability to the nanoparticles (see page 785 second column last paragraph and figure 4). In addition, Fukui et al. teach the size of the nanoparticles to reversibly change from about 400 nm to 250 nm due to cycling between incubation in deionized water or incubation in calcium chloride solution (see page 786 first column first paragraph and figure 5). Fukui et al. also note that the nanoparticles have a negative charge (see page 784 second column first full paragraph). Abodinar et al. teach that sialic acid and sulfate esters in the oligosaccharide chains of mucin are responsible for the negative charge held by its molecules (see page 281). This implies that the nanoparticles of Fukui at al. have oligosaccharide chains on their surface. The mucin molecules also contain galactose and fucose in their oligosaccharide chains (see figure 1; instant claim 2). While Fukui et al. teach the removal of some of the glycosylation, they make a point of maintaining about 80% of the original glycosylation in order to avoid undesired aggregation due to an excessive absence of these chains at the particle surface (see page 784 second column first partial paragraph; instant claim 1). Wirth et al. detail that Ulex europaeus iso-agglutinin I specifically binds a-L-fucose containing polysaccharides and employ it to demonstrate the presence of a-L-fucose in pig gastric mucin; thus a-L-fucose is also present in the mucins of Fukui et al. (see page 184 first column last partial paragraph, second column second full paragraph, page 187 second column first partial paragraph figure 2; instant claim 3). Fukui et al. teach a potential use of the crosslinked particles as carriers for cosmetic and drug compounds (see page 787 second column first partial paragraph). Covalent crosslinking is not explicitly detailed.
Hamidi et al. teach (hydro)gel nanoparticles for drug delivery (see abstract). They detail different crosslinking mechanisms for such particles and they include covalent bonds as well as non-covalent interactions such as physical entanglements and hydrophobic interactions (see page 1639 second column first partial paragraph and 1642 first column last full paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to also employ a covalent crosslinking mechanism in the nanoparticles of Fukui et al. in light of Hamidi et al. This modification would have been obvious so as to provide an additional avenue of control to the particle stability/degradation rate to facilitate a wider array of options for later use. The indicated desire for more stable nanoparticles is supported by the teaching of Fukui et al. that added further crosslinking avenues beyond their initial pH induced interactions. The sizing of nanoparticles rendered obvious by the modified teachings of Fukui et al. overlap with the instantly disclosed range of 100 to 400 nm for the instant nanoparticles, thereby rendering the requisite size obvious (see instant specification page 12 lines 29-30). “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed.Cir. 1990)” (see MPEP 2144.05). Given the teaching by Fukui et al. that their nanoparticles are charged, the nanoparticles are surface glycosylated. Some of the negatively charges sialic acid and sulphate groups of the oligosaccharides interact with the cations responsible for the particle formation such that some oligosaccharide chains of the mucin molecules are not on the surface (see Fukui et al. page 784 second column first full paragraph). As a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith. In re Brown, 459 F.2d 531, 535, 173 USPQ 685, 688 (CCPA 1972). Like the instant applicant, Fukui et al. employ a water based procedure, in the absence of a hydrophobic phase, to induce the formation of the nanoparticles from mucin (see instant specification example 1). According to MPEP 2145II, mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979). In addition, the fact that an inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Thus in the absence of evidence to the contrary, the nanoparticles of Fukui et al. in view of Hamidi et al. would have a degree of surface glycosylation as instantly claimed. Therefore claims 1-3 and 33 are obvious over Fukui et al. in view of Hamidi et al. as evidenced by Wirth et al. and Abodinar et al.
Claims 1-3, 5-6, and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Fukui et al. in view of Barthelmes et al. (previously cited) and Ofokansi et al. (previously cited) as evidenced by Wirth et al. and Abodinar et al.
Fukui et al. teach mucin gel nanoparticles that are composed of pig gastric mucin (see abstract, page 783 first column first paragraph and second column first full paragraph). The nanoparticles are formed due to electrostatic interactions with an added cationic surfactant, where the size is as small as 100 nm and increases with increasing surfactant concentration (see page 784 second column first full paragraph figure 2). They teach that the removal of the surfactant at acidic pH results in an increase in the nanoparticle size where nanoparticles that began at 250 nm grew to 470 nm once the surfactant was removed (see page 784 second column last partial paragraph). The occurrence of physical chain entanglement is suggested as being responsible for the maintenance of a particle form in spite of the swelling (see page 785 first column first partial paragraph). They go on to detail further crosslinking via chain entanglement that is induced due to heat; however, it does not overcome the swelling phenomenon upon removal of the surfactant (see page 785 second column last partial paragraph). The additional crosslinking provides added stability to the nanoparticles (see page 785 second column last paragraph and figure 4). Fukui et al. also note that the nanoparticles have a negative charge (see page 784 second column first full paragraph). Abodinar et al. teach that sialic acid and sulfate esters in the oligosaccharide chains of mucin are responsible for the negative charge held by its molecules (see page 281). This implies that the nanoparticles of Fukui at al. have oligosaccharide chains on their surface. The mucin molecules also contain galactose and fucose in their oligosaccharide chains (see figure 1; instant claim 2). While Fukui et al. teach the removal of some of the glycosylation, they make a point of maintaining about 80% of the original glycosylation in order to avoid undesired aggregation due to an excessive absence of these chains at the particle surface (see page 784 second column first partial paragraph; instant claim 1). Wirth et al. detail that Ulex europaeus iso-agglutinin I specifically binds a-L-fucose containing polysaccharides and employ it to demonstrate the presence of a-L-fucose in pig gastric mucin; thus a-L-fucose is also present in the mucins of Fukui et al. (see page 184 first column last partial paragraph, second column second full paragraph, page 187 second column first partial paragraph figure 2; instant claim 3). Fukui et al. teach a potential use of the multi-crosslinked particles as carriers for cosmetic and drug compounds (see page 787 second column first partial paragraph). Covalent crosslinking is not explicitly detailed.
Barthelmes et al. teach hydrogel nanoparticles envisioned as drug carriers (see abstract). Here, the constituent polysaccharide is electrostatically crosslinked into nanoparticles, but a shift in pH prompts their disintegration/rupture (see page 613 second column and figure 2). Barthelmes et al. teach covalently crosslinking the nanoparticles that are electrostatically crosslinked and the presence of covalent crosslinks maintains the particle size, in spite of the removal of the electrostatic crosslinking agent at acidic pH (see page 616 second column first partial paragraph and figures 1-2).
Ofokansi et al. teach microparticles composed of a 1:1 admixture of gelatin and mucin (see page 826 second column last partial paragraph-page 827 first column first partial paragraph). The particles are envisioned for mucosal delivery of contained cefuroxime that is facilitated by via their mucoadhesive properties (see page 826 first column last partial paragraph-second column first partial paragraph; instant claim 5-6). In addition, Ofokansi et al. covalently crosslink the microparticles with glutaraldehyde (see page 827 first column first full paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to covalently crosslink the nanoparticles of Fukui et al. via glutaraldehyde in order control their size and permit retention of the original size induced via electrostatic crosslinking/interactions. This modification would have been obvious in light of Barthelmes et al. who teach the improvement in size stability produced by the inclusion of covalent crosslinks in electrostatically crosslinked nanoparticles and Ofokansi et al. who teach glutaraldehyde as a covalent crosslinking agent for mucin particles. These choices are also obvious as the application of the same technique to a similar product in order to yield the same improvement. The sizing of nanoparticles rendered obvious by the modified teachings of Fukui et al. overlap with the instantly disclosed range of 100 to 400 nm for the instant nanoparticles, thereby rendering the requisite size obvious (see instant specification page 12 lines 29-30; MPEP 2144.05). Given the teaching by Fukui et al. that their nanoparticles are charged, the nanoparticles are surface glycosylated. Some of the negatively charges sialic acid and sulphate groups of the oligosaccharides interact with the cations responsible for the particle formation such that some oligosaccharide chains of the mucin molecules are not on the surface (see Fukui et al. page 784 second column first full paragraph). As a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith. In re Brown, 459 F.2d 531, 535, 173 USPQ 685, 688 (CCPA 1972). Like the instant applicant, Fukui et al. employ a water based procedure, in the absence of a hydrophobic phase, to induce the formation of the nanoparticles from mucin. According to MPEP 2145II, mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979). In addition, the fact that an inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Thus in the absence of evidence to the contrary, the nanoparticles of Fukui et al. in view of Barthelmes et al. and Ofokansi et al. would have a degree of surface glycosylation as instantly claimed. In an additional embodiment, it also would have been obvious to include cefuroxime as a drug in the nanoparticles in light of Ofokansi et al. who teach its delivery from similar mucin gel particles. Therefore claims 1-3, 5-6, and 33 are obvious over Fukui et al. in view of Barthelmes et al. and Ofokansi et al. as evidenced by Wirth et al. and Abodinar et al.
Declaration
The declaration under 37 CFR 1.132 filed October 24, 2025 is insufficient to overcome the rejection of claims 1-3 and 5-6 based upon Fukui et al. in view of others as set forth in the last Office action because:
The declarant argues that the covalently crosslinked version of the mucin nanoparticles of Fukui et al. would not be surface glycosylated because they discuss removing glycans from their mucin and do not discuss the presence of glycans on the nanoparticle surface. Fukui et al. prepare their nanoparticle from mucin from which 20% of the sugar chains have been removed (see page 784 second column first partial paragraph). This leaves the majority of the original sugar chains present. More importantly, the absolute amount of glycosylation present on the nanoparticle does not matter in regards to meeting the instant claim limitations because the degree of glycosylation is based upon a comparison to the mucin before and after formation of the nanoparticles. Further, the absence of a discussion about surface glycans on the nanoparticles of Fukui et al. is not equivalent to the absence of surface glycans on the nanoparticles of Fukui et al. As noted in MPEP 2112(I), “[t]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999).
The declarant additionally suggests that Fukui et al. points to the sugar chains of their nanoparticles being in the center of their nanoparticles. However, the section of Fukui et al. that the declarant references is discussing the response of a lysozyme loaded version of the nanoparticles to incubation in calcium chloride solution as compared to sodium chloride solution. This text that discusses the calcium chloride shrinking the nanoparticles and bringing sugar chains of the mucin closer to the lysozyme is not an indication of how many of the sugar chains are in the interior of the nanoparticles.
The declarant further conjectures that the carbohydrate chains in the mucin nanoparticles of Fukui et al. fold inward creating a hydrophilic core and hydrophobic shell from the protein backbones. There is no evidence to support such an occurrence and no clear driving force to encourage such an orientation, given that nanoparticles are made in the absence of a hydrophobic solvent. To the contrary, Fukui et al. note that their nanoparticles have a negative charge which implies that its negative charge carrying entities are on the surface. As noted in the updated rejection, the sugar chains of mucin are responsible for the negative charge it carries. Thus the evidence supports the presence of glycosylation on the surface of the nanoparticles of Fukui et al.
The declarant also suggests that crosslinking via glutaraldehyde may mask glycans. No evidence is offered to support this position or its applicability to the specific nanoparticles of Fukui et al. Moreover, the instant applicant employes glutaraldehyde to form covalent crosslinks of the instant nanoparticles (see specification example 1). Thus it is clearly viable to generate mucin nanoparticle via this well-known crosslinking agent and it can retain surface glycans.
The declarant also suggests that ethanol and acetone desolvation can disrupt glycosidic bonds. The relevance of this suggestion to the rejection is not clear, given that neither solvent is relied upon by Fukui et al. to prepare their nanoparticles.
The declarant additionally discusses benefits of the instant invention such as one pot synthesis, structural retention, and functionalization that they assert are unexpected and surprising over Fukui et al. The claims under examination are directed to a product, therefore the utility of a one-pot or multi-pot preparation technique is not relevant. Further, the declarant does not set forth the expected degree of glycosylation or the attained degree of glycosylation in the nanoparticles of Fukui et al. Therefore there is no basis to conclude that the degree of glycosylation obtained by the declarant is unexpected or surprising over Fukui et al.
The declarant goes on to discuss an assessment of surface glycosylation of mucin nanoparticles provided at four different concentrations in suspension. An equal concentration of native porcine gastric mucin in the same suspending medium is also assessed for glycosylation. The data appear to show that the same nanoparticles provided at different concentrations yield different degrees of surface glycosylation. This is suggestive that a single set of mucin nanoparticle can be both inside and outside the claim scope, depending on how glycosylation is assessed (e.g., the suspension concentration changes the measured surface glycosylation). The data also appear to show the presence of glycosylation on the tested nanoparticles. These data do not indicate the degree of glycosylation expected from a mucin nanoparticle and the instant nanoparticles yielding an unexpected amount of glycosylation comparatively nor that the Fukui et al. nanoparticles fail to achieve surface glycosylation in accordance with the instant claims.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Response to Arguments
Applicant's arguments filed October 25, 2025 have been fully considered. In light of the amendment to the claims and specification, the objection to the claims and the rejection under 35 USC 112 are hereby withdrawn. The arguments directed toward the rejections under 35 USC 103 are not persuasive. The arguments repeat the statements and discussion of the declaration. The declaration was addressed in the Declaration section above and the response is similarly reiterated.
Conclusion
No claim is 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 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 CARALYNNE E HELM whose telephone number is (571)270-3506. The examiner can normally be reached Mon-Fri 9-5.
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/CARALYNNE E HELM/Examiner, Art Unit 1615
/MELISSA S MERCIER/Primary Examiner, Art Unit 1615