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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05/07/2026 has been entered.
Status of the Claims
Claims 1-14 are pending and under current examination.
All rejections not reiterated have been withdrawn.
The claims are examined in view of the species Escherichia coli, elected without traverse.
Drawings
The drawings are objected to under 37 CFR 1.83(a) because they fail to show the text describing the samples evaluated as described in the specification. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). 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 1-14 are rejected under 35 U.S.C. 103 as being unpatentable over De Miguel (FR 2803526; publication date: 07/13/2001; citing the English machine translation; cited in the IDS filed 01/10/2023) in view of Bauer et al. (US 8,236,522; issue date: 08/07/2012).
The claim are examined in view of the elected species of pathogen/antigen: Escherichia coli.
De Miguel discloses polysaccharide particles (abstract) formed from polysaccharides or oligosaccharides such as dextran, chitosan, starch, amylose, cellulose, polygalactose, polymannose and their derivatives (page 2) which can be crosslinked and are made charged by reaction with negatively or positively charged groups (page 3). To impart a positive charge to the polysaccharide particle, it can be reacted with, inter alia, quaternary ammonium compounds (page 3). The polysaccharides are useful for oral delivery of actives including antigens for a vaccine (page 4). The active may be introduced into the polymer matrices at different stages of manufacture, depending on charge and hydrophobicity (page 4).
With regard to instant claim 1, On pages 5-9, De Miguel discloses several example methods of forming the polysaccharide particles, loaded with active agent and/or negatively charged phospholipid. Examples 3, 6, and 9 altogether, describe amphotericin B combined with the cationic polysaccharide matrix particles. Example 3 describes preparation of submicron cationic hydrophilic matrices: Inter alia, maltodextrin is crosslinked with epichorohydrin then formed into particles that are combined with the quaternary ammonium compound glycidyltrimethylammonium. Particles thus formed are homogenized to a size of less than 100 and purified by filtration (page 5). In example 6 the submicron cationic amphiphilic matrices of example 3 are associated with anionic phospholipid (dipalmitoylphosphatidylglycerol; page 6). In example 9, an aqueous solution containing the particles formed in example 6 are stirred in a water bath (i.e. an aqueous solution comprising a cationic nanoparticle consisting of a porous cationic polysaccharide core is provided), and this is combined with a solution of amphotericin B followed by stirring for 2 hours (i.e. an active agent is added to the aqueous solution), which results in association of amphotericin B with the particles (page 8).
De Miguel does not disclose that the vaccine antigen has been lyophilized nor is the elected species of antigen, Escherichia coli, disclosed.
Bauer discloses a bacterial extract as a vaccine to reduce incidence of digestive or urinary tract infections cause by Escherichia coli (E. coli) that contain lysates of E. coli (title, abstract, col 1, lines 27-31) for oral delivery (col 9, lines 5-7). The lysate of E. coli is lyophilized then recovered (col 23, lines 30-60). Bauer then teaches oral administration of this lyophilizate (see e.g. col 27, lines 57-59).
It would have been prima facie obvious to formulate the lyophilized lysate of E. coli described by Bauer into De Miguel’s vehicle. The skilled artisan would have been motivated to do so in order to provide the advantages described by De Miguel of stability and protection from the surrounding environment as well as controlled delivery (page 4). The skilled artisan would have had a reasonable expectation of success because De Miguel indicates the vehicle to be suitable for antigens for a vaccine (page 4).
With regard to the limitation recited in instant claim 1, as amended, requiring “solubilizing the at least on lyophilized antigen at ambient temperature”, the examiner notes that in De Miguel’s examples, using highly hydrophobic drugs, the step of solubilizing the active substance is performed above room temperature. The examiner also points out that De Miguel teaches that the active agent is in solution when it is associated with the particles. Thus, the artisan having ordinary skill, a highly intelligent person with e.g. a Ph.D. degree, would have sought to ensure that the active agent is dissolved when it is combined with the particles in De Miguel’s method.
Bauer teaches that the E. coli lysates can be dissolved in water at room temperature: “the extracts were dissolved … in distilled water” (col 29, lines 7-9).
It would have been prima facie obvious to carry out the solubilizing step taught by Miguel at whatever temperature was required to solubilize the specific active agent in question. In the case of the E. coli extracts taught by Bauer, one having ordinary skill would have recognized that this step may be carried out at room temperature, and the heating step used to solubilize amphotericin or estradiol valerate because the E. coli lyophilizate is soluble in water at ambient temperature. For this reason, the examiner does not consider the requirement that the solubilizing step occur at ambient temperature to patentably define over the cited prior art. See also MPEP 2144.05(II): Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
With regard to claim 2, upon addition of the freeze-dried E. coli lysate, noted above, the aqueous solution would contain an antigenic protein from E. coli.
With regard to claim 3, De Miguel discloses an example in which the polysaccharide is not crosslinked (see example 12).
With regard to claims 3, 4, and 6, as noted above an example polysaccharide core is formed with maltodextrin and the quaternary ammonium compound glycidyltrimethylammonium.
With regard to claims 4 and 5, as noted above, the polysaccharide is crosslinked with epichlorohydrin.
With regard to claims 7-9, in the example noted above, the particle is charged with dipalmitoylphosphatidylglycerol.
With regard to claim 10, in other examples the particles are not charged with lipid, see e.g. example 2. The examiner considers this an obvious variant of the procedure disclosed by De Miguel.
With regard to claims 11-14, the antigen in the method rendered obvious by De Miguel and Bauer is a lysate (i.e. an extract) of the bacterial pathogen, Escherichia coli.
Response to Arguments
Applicant's arguments filed 06/11/2026 and 05/07/2026 have been fully considered but they are not persuasive.
Response to remarks filed 06/11/2026
On page 8, Applicant argues the claimed nanoparticles are active participants in the solubilization process. On page 9, Applicant argues that the Office action fails to establish why one of ordinary skill would have been motivated to modify the nanoparticle systems of De Miguel in such a manner that the nanoparticles themselves would participate in the solubilization of a lyophilized antigen. On page 9, Applicant argues that neither De Miguel nor Bauer recognize or solve the same problem as that of the instant application. On page 8, Applicant argues that it is possible to solubilize lyophilized antigens without the addition of conventional lyophilization aids or solubilizing agents. On page 8, Applicant argues that the present application addresses the need for solubilizing lyophilized antigens intended for vaccine use without relying on conventional solubilization aids or lyophilization excipients and that neither De Miguel nor Bauer teach this functionality or the reconstitution or solubilization of a lyophilized antigen in a nanoparticle containing aqueous solution. On page 9, Applicant argues that one would have lacked reasonable expectation of success in achieving increased solubility of a lyophilized antigen in the presence of the claimed cationic porous polymer nanoparticle. On page 10, Applicant argues that the present application achieves solubilization of lyophilized antigens without requiring conventional solubilization aids.
The assertion that the nanoparticles participate in the solubilization process appears to be speculative, based upon the current data of record, no experiments (that are currently legible on the record) evaluate such a phenomenon. The examiner notes that the tables in the specification are barely legible and the figures are illegible in the copy of the application currently on file with the USPTO. Moreover, in response to applicant's argument that the particles participate in the solubilization of the lyophilized antigen and that one would have lacked reasonable expectation of success in achieving increased solubility of a lyophilized antigen in the presence of the claimed cationic porous polymer nanoparticle, the fact that the 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. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). As the particles taught by De Miguel fall entirely within the scope of the instant claims, the property of binding/solubilizing lyophilized antigens appears to be a property of the prior art particles.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., solubilizing lyophilized antigens intended for vaccine use without relying on conventional solubilization aids or lyophilization excipients) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The claims currently recite an open preamble and therefore do not exclude solubilization aids or lyophilization excipients. Nor does the record establish that such were lacking from the lyophilized E. coli lysate used to in the experiments described in the specification.
Insomuch as the argument that neither De Miguel nor Bauer recognize or solve the same problem as that of the instant application may be an assertion that De Miguel and Bauer are non-analogous art, the examiner respectfully disagrees. De Miguel is directed to lipid charged cationic polysaccharide nanoparticles for delivery of bioactives including antigens and Bauer is directed to E. coli lyophilizates for vaccines. As such, both references are in the same field of endeavor and address the same problem as Applicant: formulation of antigens for vaccine delivery.
Insomuch as the argument that one would have lacked reasonable expectation of success in achieving increased solubility of a lyophilized antigen in the presence of the claimed cationic porous polymer nanoparticle is an assertion of unexpected results, please see further discussion below regarding the burden on applicant to overcome an obviousness rejection with a persuasive showing of unexpected results.
On page 10, Applicant argues that absent knowledge of Applicant’s disclosure, the cited references do not provide a teaching or rationale that would have led a person of ordinary skill in the art to attribute such a solubilizing function to the nanoparticles of De Miguel.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Response to remarks filed 05/07/2026
On pages 10-12, Applicant replicates sections of Bauer’s disclosure in support of the assertion that Bauer does not disclose lyophilized extract in solid form but rather the extracts of Bauer are in the form of a solution.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., the prior art not teaching the lyophilizate in solid form) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Moreover, Bauer unambiguously teaches an E. coli lyophilizate in example 4.17: e.g. “The lyophilizate was sifted through a fitted vibrating sieve. 11.95 kg of lyophilizate were recovered.” Also, the claims recite “solubilizing the antigen in aqueous solution and incubating a composition thus obtained”. This does not exclude a step of first dissolving the lyophilizate, and in the event the claims were amended to require such, changes in sequence of adding ingredients are prima facie obvious (see MPEP 2144.04(IV)(C)), to include dissolving in one step vs. multiple steps.
On page 13, Applicant argues that lyophilized proteins are difficult to reconstitute due to their propensity to aggregate, denature, or precipitate on contact with aqueous media and for this reason the skilled person routinely relies on addition of dedicated solubilizing or stabilizing agents. Applicant argues further that the present invention is directed to cationic nanoparticles that directly interact with lyophilized antigen to achieve solubilization and this is surprising in view of the diversity of the antigens which may vary widely in size, charge, and hydrophobicity. Applicant argues that the nanoparticles provide multiple functions including solubilization, stabilization of the antigen and facilitation of delivery to immune cells, and that these features are not suggested in the prior art. Applicant argues that the claimed method goes beyond mere alternative formulation and provides a practical advantage that would not have been anticipated based on the teachings of the prior art. Applicant argues that the results demonstrated the claimed method achieves a technical effect that is both unexpected and advantageous, and therefore the instant claims are nonobvious over De Miguel and Bauer.
Insomuch as this may be an assertion of unexpected results, please refer to MPEP 716.02(b) which details the burden on Applicant to establish that results in a side-by-side comparison to the closest prior art are unexpected and significant. Specifically, Applicant must establish that differences in results are in fact unexpected and unobvious and are of both practical and statistical significance. Additionally, evidence of unexpected properties must be commensurate in scope with the claims.
In the instant case the practical significance of the data has not been established as the record does not make clear that the E coli lysate bound to the nanoparticles shows efficacy as a vaccine. The data are not commensurate in scope with the claims. The claims embrace any polysaccharide-containing nanoparticle so long as there is at least one positive charge associated with it and any lyophilized antigen; however, data are only shown for nanoparticles formed from maltodextrin, crosslinked with epichlorohydrin, or uncrosslinked, and charged with GTMA. These two nanoparticles are either used directedly or charged with a single substance of phospholipid, DPPG (see pages 13-14 of the instant specification). Neither data nor reasoned argument support that the observations presented in the specification would construe across the full scope of the claims. Additionally, the experiments do not provide a clear nexus with any allegedly unexpectedly superior property (e.g. solubilization of a lyophilized antigen) and the difference between the claimed invention and the closest prior art in a side-by-side comparison. De Miguel discloses a particle falling entirely within the scope of the instant claims and proposes its use for vaccine/antigen delivery. The difference between the closest prior art and the claimed invention is that the vaccine/antigen was lyophilized. No comparison is made between a lyophilized vs. non-lyophilized antigen, as such, no clear improvement over the prior art has been made of record. The examiner also points out that the text in tables in the specification is very difficult to read because of the poor quality of the images and the drawing text is wholly illegible. This further confounds analysis of the allegedly unexpectedly superior results. Finally, the examiner points out that E. coli lysates contain many substances alleged to improve solubility of the proteins contained therein, such as amino acids and sugars (see Bauer, col 23, lines 30-60). For this reason as well with regard to the solubilization of lyophilized E. coli lysate, it is unclear whether an unexpected property has been described.
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 1-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over
claims 1-8 of U.S. Patent No. 6759060;
claims 1-29 of U.S. Patent No. 6342226;
claims 1-30 of U.S. Patent No. 6214621;
claims 1-48 of U.S. Patent No. 6017513;
claims 1-37 of U.S. Patent No. 6096291; and
claims 1-20 of U.S. Patent No. 9731005
in view of Miguel (FR 2803526; publication date: 07/13/2001; citing the English machine translation; cited in the IDS filed 01/10/2023) in view of Bauer et al. (US 8,236,522; issue date: 08/07/2012).
Inter alia, the claims of the cited patents embrace a particle for vaccine or biologically active agent delivery comprising a solid nanoparticle formed from a polysaccharide selected from dextran, a dextrin, and a maltodextrin and a cationic group such as a quaternary ammonium group and further associated with a negatively charged phospholipid.
The claims of the cited patents do not disclose a method for forming the solid particle component.
De Miguel discloses polysaccharide particles (abstract) formed from polysaccharides or oligosaccharides such as dextran, chitosan, starch, amylose, cellulose, polygalactose, polymannose and their derivatives (page 2) which can be crosslinked and are made charged by reaction with negatively or positively charged groups (page 3). To impart a positive charge to the polysaccharide particle, it can be reacted with, inter alia, quaternary ammonium compounds (page 3). The polysaccharides are useful for oral delivery of actives including antigens for a vaccine (page 4). The active may be introduced into the polymer matrices at different stages of manufacture, depending on charge and hydrophobicity (page 4). Thus, the particles are comparable to those of the cited patents.
On pages 5-9, De Miguel discloses several example methods of forming the polysaccharide particles, loaded with active agent and/or negatively charged phospholipid. Examples 3, 6, and 9 altogether, describe amphotericin B combined with the cationic polysaccharide matrix particles. Example 3 describes preparation of submicron cationic hydrophilic matrices: Inter alia, maltodextrin is crosslinked with epichorohydrin then formed into particles that are combined with the quaternary ammonium compound glycidyltrimethylammonium. Particles thus formed are homogenized to a size of less than 100 and purified by filtration (page 5). In example 6 the submicron cationic amphiphilic matrices of example 3 are associated with anionic phospholipid (dipalmitoylphosphatidylglycerol; page 6). In example 9, an aqueous solution containing the particles formed in example 6 are stirred in a water bath (i.e. an aqueous solution comprising a cationic nanoparticle consisting of a porous cationic polysaccharide core is provided), and this is combined with a solution of amphotericin B followed by stirring for 2 hours (i.e. an active agent is added to the aqueous solution), which results in association of amphotericin B with the particles (page 8).
It would have been prima facie obvious to form the solid polysaccharide core according to the method disclosed by De Miguel because this would have been simply combining prior art elements according to known methods to yield predictable results (see MPEP 2143(A)).
Neither the cited patents nor De Miguel disclose that the vaccine antigen to be combined with the particles has been lyophilized nor is the elected species of antigen, Escherichia coli, disclosed.
Bauer discloses a bacterial extract as a vaccine to reduce incidence of digestive or urinary tract infections cause by Escherichia coli (E. coli) that contain lysates of E. coli (title, abstract, col 1, lines 27-31) for oral delivery (col 9, lines 5-7). The lysate of E. coli is lyophilized then recovered (col 23, lines 30-60). Bauer then teaches oral administration of this lyophilizate (see e.g. col 27, lines 57-59).
It would have been prima facie obvious to formulate the lyophilized lysate of E. coli described by Bauer into De Miguel’s vehicle. The skilled artisan would have been motivated to do so in order to provide the advantages described by De Miguel of stability and protection from the surrounding environment as well as controlled delivery (page 4). The skilled artisan would have had a reasonable expectation of success because De Miguel indicates the vehicle to be suitable for antigens for a vaccine (page 4).
With regard to the limitation recited in instant claim 1, as amended, requiring “solubilizing the at least on lyophilized antigen at ambient temperature”, the examiner notes that in De Miguel’s examples, using highly hydrophobic drugs, the step of solubilizing the active substance is performed above room temperature. The examiner also points out that De Miguel teaches that the active agent is in solution when it is associated with the particles. Thus, the artisan having ordinary skill, a highly intelligent person with e.g. a Ph.D. degree, would have sought to ensure that the active agent is dissolved when it is combined with the particles in De Miguel’s method.
Bauer teaches that the E. coli lysates can be dissolved in water at room temperature: “the extracts were dissolved … in distilled water” (col 29, lines 7-9).
It would have been prima facie obvious to carry out the solubilizing step taught by Miguel at whatever temperature was required to solubilize the specific active agent in question. In the case of the E. coli extracts taught by Bauer, one having ordinary skill would have recognized that this step may be carried out at room temperature, and the heating step used to solubilize amphotericin or estradiol valerate because the E. coli lyophilizate is soluble in water at ambient temperature. For this reason, the examiner does not consider the requirement that the solubilizing step occur at ambient temperature to patentably define over the cited prior art. See also MPEP 2144.05(II): Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
With regard to claim 2, upon addition of the freeze-dried E. coli lysate, noted above, the aqueous solution would contain an antigenic protein from E. coli.
With regard to claim 3, De Miguel discloses an example in which the polysaccharide is not crosslinked (see example 12). The examiner considers non-crosslinked particles to have been an obvious variant of the cited patents.
With regard to claims 3, 4, and 6, as noted above an example polysaccharide core is formed with maltodextrin and the quaternary ammonium compound glycidyltrimethylammonium.
With regard to claims 4 and 5, as noted above, the polysaccharide is crosslinked with epichlorohydrin.
With regard to claims 7-9, in the example noted above, the particle is charged with dipalmitoylphosphatidylglycerol.
With regard to claim 10, in other examples the particles are not charged with lipid, see e.g. example 2.
With regard to claims 11-14, the antigen in the method rendered obvious by De Miguel and Bauer is a lysate (i.e. an extract) of the bacterial pathogen, Escherichia coli.
Claims 1-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18251658 in view of Miguel (FR 2803526; publication date: 07/13/2001; citing the English machine translation; cited in the IDS filed 01/10/2023) in view of Bauer et al. (US 8,236,522; issue date: 08/07/2012).
Inter alia, the claims of the application embrace a particle for vaccine or biologically active agent delivery comprising a solid nanoparticle formed from a polysaccharide selected from dextran, a dextrin, and a maltodextrin and a cationic group such as a quaternary ammonium group and further associated with a negatively charged phospholipid.
The claims of the cited application do not disclose a method for forming the solid particle component.
De Miguel discloses polysaccharide particles (abstract) formed from polysaccharides or oligosaccharides such as dextran, chitosan, starch, amylose, cellulose, polygalactose, polymannose and their derivatives (page 2) which can be crosslinked and are made charged by reaction with negatively or positively charged groups (page 3). To impart a positive charge to the polysaccharide particle, it can be reacted with, inter alia, quaternary ammonium compounds (page 3). The polysaccharides are useful for oral delivery of actives including antigens for a vaccine (page 4). The active may be introduced into the polymer matrices at different stages of manufacture, depending on charge and hydrophobicity (page 4). Thus, the particles are comparable to those of the cited patents.
On pages 5-9, De Miguel discloses several example methods of forming the polysaccharide particles, loaded with active agent and/or negatively charged phospholipid. Examples 3, 6, and 9 altogether, describe amphotericin B combined with the cationic polysaccharide matrix particles. Example 3 describes preparation of submicron cationic hydrophilic matrices: Inter alia, maltodextrin is crosslinked with epichorohydrin then formed into particles that are combined with the quaternary ammonium compound glycidyltrimethylammonium. Particles thus formed are homogenized to a size of less than 100 and purified by filtration (page 5). In example 6 the submicron cationic amphiphilic matrices of example 3 are associated with anionic phospholipid (dipalmitoylphosphatidylglycerol; page 6). In example 9, an aqueous solution containing the particles formed in example 6 are stirred in a water bath (i.e. an aqueous solution comprising a cationic nanoparticle consisting of a porous cationic polysaccharide core is provided), and this is combined with a solution of amphotericin B followed by stirring for 2 hours (i.e. an active agent is added to the aqueous solution), which results in association of amphotericin B with the particles (page 8).
It would have been prima facie obvious to form the solid polysaccharide core according to the method disclosed by De Miguel because this would have been simply combining prior art elements according to known methods to yield predictable results (see MPEP 2143(A)).
Neither the cited application nor De Miguel disclose that the vaccine antigen to be combined with the particles has been lyophilized nor is the elected species of antigen, Escherichia coli, disclosed.
Bauer discloses a bacterial extract as a vaccine to reduce incidence of digestive or urinary tract infections cause by Escherichia coli (E. coli) that contain lysates of E. coli (title, abstract, col 1, lines 27-31) for oral delivery (col 9, lines 5-7). The lysate of E. coli is lyophilized then recovered (col 23, lines 30-60). Bauer then teaches oral administration of this lyophilizate (see e.g. col 27, lines 57-59).
It would have been prima facie obvious to formulate the lyophilized lysate of E. coli described by Bauer into the vehicle of the cited application. The skilled artisan would have been motivated to do so in order to provide the advantages described by De Miguel of stability and protection from the surrounding environment as well as controlled delivery (page 4). The skilled artisan would have had a reasonable expectation of success because De Miguel indicates the vehicle to be suitable for antigens for a vaccine (page 4).
With regard to the limitation recited in instant claim 1, as amended, requiring “solubilizing the at least on lyophilized antigen at ambient temperature”, the examiner notes that in De Miguel’s examples, using highly hydrophobic drugs, the step of solubilizing the active substance is performed above room temperature. The examiner also points out that De Miguel teaches that the active agent is in solution when it is associated with the particles. Thus, the artisan having ordinary skill, a highly intelligent person with e.g. a Ph.D. degree, would have sought to ensure that the active agent is dissolved when it is combined with the particles in De Miguel’s method.
Bauer teaches that the E. coli lysates can be dissolved in water at room temperature: “the extracts were dissolved … in distilled water” (col 29, lines 7-9).
It would have been prima facie obvious to carry out the solubilizing step taught by Miguel at whatever temperature was required to solubilize the specific active agent in question. In the case of the E. coli extracts taught by Bauer, one having ordinary skill would have recognized that this step may be carried out at room temperature, and the heating step used to solubilize amphotericin or estradiol valerate because the E. coli lyophilizate is soluble in water at ambient temperature. For this reason, the examiner does not consider the requirement that the solubilizing step occur at ambient temperature to patentably define over the cited prior art. See also MPEP 2144.05(II): Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
With regard to claim 2, upon addition of the freeze-dried E. coli lysate, noted above, the aqueous solution would contain an antigenic protein from E. coli.
With regard to claim 3, De Miguel discloses an example in which the polysaccharide is not crosslinked (see example 12). The examiner considers non-crosslinked particles to have been an obvious variant of the cited application.
With regard to claims 3, 4, and 6, as noted above an example polysaccharide core is formed with maltodextrin and the quaternary ammonium compound glycidyltrimethylammonium.
With regard to claims 4 and 5, as noted above, the polysaccharide is crosslinked with epichlorohydrin.
With regard to claims 7-9, in the example noted above, the particle is charged with dipalmitoylphosphatidylglycerol.
With regard to claim 10, in other examples the particles are not charged with lipid, see e.g. example 2.
With regard to claims 11-14, the antigen in the method rendered obvious by De Miguel and Bauer is a lysate (i.e. an extract) of the bacterial pathogen, Escherichia coli.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 06/11/2026 have been fully considered but they are not persuasive.
On pages 11 and 12, Applicant argues that De Miguel and Bauer do not teach the step of solubilizing the lyophilized antigen in the aqueous solution at ambient temperature.
This is not persuasive for the reasons set forth in the rejections and as described in greater detail in the Response to Arguments section following the obviousness rejection.
Conclusion
No claims are allowed.
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/KATHERINE PEEBLES/ Primary Examiner, Art Unit 1617
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