DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . 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 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.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/14/0226 has been considered by the examiner.
Status of the Claims
The response and amendment filed 01/19/2026 is acknowledged.
Claims 25-30, 32-49 and 51-66 are pending.
Claims 25 and 34 are independent.
Claims 34-42 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 06/30/2025.
Claim 57 remains withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species of adjuvant, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 06/30/2025.
Claims 25-30, 32-33, 43-49, 51-56 and 58-66 are treated here.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application. Rejections not reiterated herein have been withdrawn.
Withdrawn
The rejection of claims 25-33, 43-56 and 58-66 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subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention has been withdrawn because of Applicant’s amendment.
The rejection of claim 63 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subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention has been withdrawn because of Applicant’s amendment.
The rejection of claims 25-29, 43-51, 58-59, and 61-65 under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Hanes, WO 2015175545 A1 (cited on Applicant’s IDS dated 06/16/2023) as evidenced by Mittal, Virus Research, 28, 1, 1993 (Abstract) has been withdrawn because of Applicant’s amendment.
The rejection of claims 25-29, 43-51, 58-59, and 61-65 under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Mastorakos, PNAS, 112, 28, 2015 as evidenced by Mittal, Virus Research, 28, 1, 1993 (Abstract) has been withdrawn because of Applicant’s amendment.
Neither Hanes nor Mastorakos teach the nanoparticle composition comprising one or more adjuvants.
Response to Arguments
Applicant's arguments filed 01/19/2026 have been fully considered but they are not persuasive.
Applicant argues that the immunogenic composition, as defined in the amended claims combining adjuvants and mucus-penetrating nanoparticles, unexpectedly elicited significantly stronger adaptive immunity in the lung and other mucosal surfaces. Applicant argues the composition generated greater systemic immunity and an enhanced anti-cancer effect relative to dose-matched antigen-expressing plasmids and adjuvants co-administered via in compositions that did not include the nanoparticles required by the claims as amended (Remarks, e.g., pg. 4/8). Applicant argues unexpected results, i.e., the disclosed compositions exhibited greater systemic immunity and enhanced anti-cancer effect compared to dose matched antigen expressing plasmids and adjuvants co-administered via other common routes (Remarks, e.g., pg. 13); the enhanced systemic immunity by inhaled MPP demonstrated here was not expected a pirori (Remarks, e.g., pg. 14).
Applicant argues previous studies (Bivas-Benita, et al., J. Virol., 84:5764-5774 (2010) and Li, et al., Sci. Transl. Med. 5:204re130 (2013)) support a conclusion that the results obtained with the claimed composition are unexpected. Applicant argues the previous studies only showed that inhaled nanoparticle based DNA vaccination is capable of inducing a robust systemic immunity but to a level comparable to that achieved by intramuscular immunization, and the addition of adjuvants should improve intramuscular immunization and inhaled nanoparticle based immunization to the same extent. However, Applicant argues data in the present application demonstrates an unexpected superior effect when the adjuvant is delivered via a composition containing the disclosed nanoparticles (Remarks, e.g., pp. 11-12).
Specifically, Applicant argues (Remarks, e.g., pp. 12-13) that a nucleic acid adjuvant (unmethylated cytosine guanine (CpG)) and a second adjuvant (electroporation) as examples, Example 3 of the Specification demonstrates the superior effects shown when the adjuvant is delivered with a composition containing nanoparticles as recited in the claims, as amended. Applicant argues exemplary immunogenic composition CpG/pOVA171 MPP in example 3, administered intratracheally was compared with carrier free CpG/pOVA administered via other conventional delivery routes, e.g., intradermal administration or intramuscular injection followed by electroporation (IM-EP). Applicant argues intratracheal administration (IT) of CpG/pOVA171 MPP exhibited significantly greater OVA-specific CTL response in comparison to the other delivery routes for antigen or adjuvant. See Specification page 71, lines 16-20 and FIGs 4B-4D Applicant argues intratracheal administration (IT) of CpG/pOVA-MPP resulted in -40% of OVA-specific CTL in the lung, unlike all other control groups that exhibited negligible levels of pulmonary CTL responses. See Specification page 71 liens 20-24. Applicant argues intratracheal administration (IT) of CpG/pOVA-MPP yielded significantly greater frequencies of pulmonary and splenic CD4+ T-cell activation, compared to IT CpG/pOVA (adjuvant and antigen without nanoparticles), ID CpG/pOVA and IM-EP CpG/pOVA (adjuvant/antigen and second adjuvant) groups. See Specification, page 72 lines 4-8, and FIGs. 5A, 5B, 5D, and 5E. Applicant additionally argues example 4 of the specification compares intratracheal administration (IT) of CpG/pOVA-MPP with other carriers and/or conventional routes, intratracheal administration (IT) of CpG/pOVA (where the carrier is not nanoparticles), ID CpG/pOVA and IM-EP CpG/pOVA groups. Applicant argues the results in example 4 show that intratracheal administration (IT) of CpG/pOVA-MPP group exhibited significantly greater frequencies of OVA-specific CD8+ T-cells both in GI and vaginal tracts compared to IT CpG/pOVA, ID CpG/pOVA and IM-EP CpG/pOVA (where electroporation, a known adjuvant, is used) groups. See Specification page 74, lines 15-17, and FIGs. 6A-6C. Applicant argues Example 6 discloses that the exemplary immunogenic composition, CpG/pOVA-MPP, provided an enhanced anti-cancer effect in comparison to conventional routes, ID CpG/pOVA and IM-EP CpG/pOVA. See Specification page 77, lines 22-25 and FIG. 11B.
These arguments have been given full consideration but are unpersuasive.
It is unclear how the cited previous studies (Bivas-Benita, et al., J. Virol., 84:5764-5774 (2010) and Li, et al., Sci. Transl. Med. 5:204re130 (2013)) support a conclusion that the results obtained with the claimed composition are unexpected. Both Bivas-Benita and Liu suggest significantly stronger adaptive immunity in the lung and other mucosal surfaces was the expected result of pulmonary administration of antigens. See Bivas-Benita and Liu, e.g., Abstract. Bivas-Benita clearly teaches pulmonary immunization with a PEI-DNA complex showed greater systemic immunization than intramuscular administration. Similarly, Liu teaches pulmonary administration of lipid nanocapsules containing a protein or peptide antigen cargo and a co-cargo of two adjuvants elicited 13-fold higher T cell response compared to subcutaneous administration in mucosal sites distal from the lungs, e.g., vaginal mucosa. Neither Bivas-Benita, nor Liu, express evidence establishing expectations for mucus penetrating particles. Both Biva-Benita and Liu suggest pulmonary administration of antigens is expected to provide greater systemic immunity, irrespective of the presence of co-adjuvant in the particle (Liu) or absence of adjuvant with the antigen (Bivas-Benita).
Bivas-Benita and Liu suggest pulmonary administration of PEI-DNA nanoparticles and lipid nanocapsules were known to induce higher systemic immunity than intramuscular or subcutaneous administration. For example, Bivas-Benita teaches T-cell responses in the lymph nodes (MLN) of pulmonary immunized mice was 10 fold higher than the response in MLN of IM immunized mice (Bivas-Benita, e.g., pg. 5768, and Fig. 4b). Thus, to the extent that systemic immune response is characterized by lymph nodes (mediastinal LN, see Spec, e.g., pg. 71), the references suggest it was expected that pulmonary administration would result in higher systemic immune response relative to IM as measured in the lymph nodes.
Bivas-Benita teaches pulmonary DNA immunization is an effective strategy to generate protective immunity against respiratory pathogens, but also protects against infections that are initiated at other mucosal sites based on immune responses in the systemic and distant mucosal compartments (Bivas-Benita, e.g., pg. 5773). The proffered results appear to confirm the CTL response shows similar systemic immunity for pulmonary immunization using mucus penetrating particles known from the combined teachings of Hanes and Hipp. Since neither Bivas-Benita nor Liu discuss mucus penetrating nanoparticles, it is not clear how these references inform expectations for the systemic immunity difference between mucus penetrating particles administered intratracheally (pulmonary) and carrier free adjuvanted plasmid DNA administered IM or ID. However, the proffered results appear to be the expected improved systemic immunity from pulmonary administration based on findings of Bivas-Benita and Liu.
The disclosed invention has not been compared to either Bivas-Benita’s PEI-DNA complex or Liu’s antigen carrying lipid nanocapsules.
Regarding Applicant’s argument (Remarks, e.g., ppg. 12-13) that using a nucleic acid adjuvant (unmethylated cytosine guanine (CpG)) and a second adjuvant (electroporation) as examples, Example 3 of the Specification demonstrates the superior effects shown when the adjuvant is delivered with a composition containing nanoparticles as recited in the claims: This is not an apples-to-apples comparison at least because CpG/pOVA is not complexed or cargo in a nanoparticle. The claims are directed to the nanoparticles themselves rather than a method requiring intratracheal administration. Therefore, the comparison is of little probative value to the claimed invention. The CTL (cytotoxic T cell) response related in example 3, pg. 71:3-23 is a comparison of CpG/pOVA-MPP (mucus penetrating nanoparticle comprising adjuvant (CpG) and antigen plasmid (pOVA)) compared to a carrier free CpG/pOVA via different delivery routes. This also is not an apples-to-apples comparison at least because the comparative carrier free antigen/adjuvant combination is not in a mucus penetrating nanoparticle, i.e., is carrier free, and because the routes of administration are not the same. Since neither Bivas-Benita nor Liu relate to mucus penetrating particles or the exemplified antigen, it is not clear how these references can establish expectations for mucus penetrating particles having the exemplified antigens. Further, since the closest prior art is a mucus penetrating particle without an adjuvant co-encapsulated with the antigen, it is not clear how Example 3 is a comparison with the closest prior art.
Example 4 is also a comparison of carrier free CpG/pOVA with mucus penetrating particles comprising CpG/pOVA cargoes. The closest prior art is a mucus penetrating particle without an adjuvant co-encapsulated with the antigen, it is not clear how Example 4 is a comparison with the closest prior art.
Example 6 is also a comparison of carrier free CpG/pOVA with mucus penetrating particles comprising CpG/pOVA cargoes using different routes of administration. The closest prior art is a mucus penetrating particle without an adjuvant co-encapsulated with the antigen, it is not clear how Example 6 is a comparison with the closest prior art.
The claimed invention is not commensurate in scope with the proffered results.
Applicant’s arguments refer only to the system described in the above referenced application and not to the individual claims of the application. As such, the examples of the specification do not show that the objective evidence of nonobviousness is commensurate in scope with the claims. See MPEP § 716, e.g., 716.02(d).
The claimed invention is directed to an immunogenic composition comprising one or more adjuvants and mucus penetrating nanoparticles rather than a method of immunization comprising intratracheal administration of the composition.
All of the proffered results argued in the Remarks have been shown with a single, specific embodiment, i.e., CpG/pOVA-MPP. This is a specific nanoparticle composition as seen in Example 1, e.g., pp. 59-60. In the examined specification, the biodegradable polymer is a specific PBAE and the hydrophilic polymer is methoxy PEG. The PBAE is based on 1,4-butanediol diacrylate and amine alcohols, e.g., 4-amino-1-butanol). The antigen is a plasmid nucleic acid encoding polypeptide (OVA expressing plasmid). The adjuvant is CpG. The polymer mixture of the nanoparticle is a specific blend of a specific PBAE alone with the same specific PBAE conjugated to PEG at a wt/wt ratio of 2:3 based on the mass of PBAE (Spec., e.g., pg. 60: DNA-loaded nanoparticle formulation & characterization). The adjuvant of the exemplified MPP is also co-packaged with the plasmid antigen. See specification, e.g., pg. 40, compare pOVA-MPP with CpG/pOVA-MPP in table. The specification indicates the methoxy PEG conjugated PBAE is approximately 4kDa and the conjugated methoxy PEG is 5 kDa, while the non-PEGylated PBAE is approximately 6kDa. The mass ratio between PEG:PBAE is 3:2. See Specification, e.g., pg. 19:9-20. The specification indicates all of these variables have been optimized for desired physicochemical properties, e.g., increased stability and transfection efficiency (Spec, e.g., pg. 16:22-31, pg. 41:25-31, pg. 42:9-30). Further, the mass ratio of blended polymer to cargo has been optimized for producing the desired physicochemical properties of colloidally stable nanoparticles with a diameter of less than 100 nm and near neutral surface charge (Specification, e.g., pg. 43).
In contrast, the claimed immunogenic composition requires: 1) the composition, not the nanoparticles, comprise “one or more adjuvants” rather than then CpG adjuvant of the disclosed composition, and 2) mucus penetrating nanoparticles formed of a biodegradable polymer and a hydrophilic polymer. Claim 25 does not require a blend of non-conjugated PBAE (biodegradable polymer) and PBAE conjugated to methoxy PEG, e.g., all of the biodegradable polymer may be conjugated to the hydrophilic polymer (> 50% reads on 100%). The claimed biodegradable polymer is not limited to the PBAE based on 4-amino-1 butanol and 1,4-butanediol diacrylate exemplified to obtain the proffered results. The claimed “hydrophilic polymer” is not limited to methoxy PEG used to obtain the proffered results (Spec, e.g., pg. 18:6-15, pg. 41:12-20, and Example 1, polymer synthesis, pg. 59). The claimed invention is silent to the 2:3 mass ratio of PBAE to PBAE-PEG blend used to obtain the proffered results. The specification states the disclosed mass ratios are optimized to produce colloidally stable nanoparticles with a diameter of less than 100 nm and a near neutral surface charge (Specification, e.g., pg. 43). These features are only required separately in claims 61-62. The claims are silent to the mass ratio of blended polymer to cargo. Formulated for pulmonary administration is only required separately in dependent claim 28. The amount of nanoparticles effective to increase systemic immunity is only required separately in dependent claim 44. The molecular weights for the biodegradable polymer and hydrophilic polymer are only required separately in claims 63 and 65. The adjuvant of claim 25 is not required to be in the core of the mucus penetrating nanoparticle which is the arrangement used to obtain the proffered results. Claim 25 does not require the co-packaged adjuvant arrangement used to obtain the proffered results. There is no data for situations wherein the adjuvant is loaded into different nanoparticles from the antigen or nucleic acid encoding the antigen, or wherein the adjuvant is not loaded into nanoparticles as allowed by claims 32 and 33. The specification suggests these arrangements do not all exhibit the same properties (Spec, e.g., pg. 22:17-25: efficient mucus penetration of MPPs is essential for particle access and uptake by pulmonary DC). There is insufficient data to support unexpected results over the full scope of the adjuvants encompassed by claims 25 and 52.
Although the specification asserts the formulation methods can be applied to various biodegradable cationic polymers (Spec, e.g., pg. 40), the claimed invention is not limited to the cationic biodegradable polymers (PBAE based on 4-amino-1 butanol and 1,4-butanediol diacrylate) with particular molecular weights exemplified to obtain the proffered results. Further, there is no objective evidence for any other biodegradable polymer or cationic biodegradable polymer showing the results may be extrapolated over the full scope of the claimed invention.
The specification also suggests the physiochemical properties of the nanoparticles depend on factors including the mass ratio of free polymer and conjugated polymer within the blended polymer; the mass ratio of cargo to blended polymer; the mass ratio of nucleic acid to adjuvant; the volume ratio of cargo added to the blended polymer; the rate at which cargo and blended polymer are combined, and the concentration ratio of the cargo to the blended polymer. See specification, e.g., pg. 42:1-7).
The proffered results are dependent on mucus penetrating properties imparted by the physicochemical properties characteristic to the composition of the nanoparticles:
a densely coated particle is formed from a ratio of polyethylene glycol to polymer that is sufficient to alter the physicochemical properties of the particle relative to a less densely coated, or non-coated particle (Spec, e.g., pg. 13, 19-30)
the MPPs exemplified exhibit physicochemical characteristics, including hydrodynamic diameter, polydispersity index, surface charge, colloidal stability, near neutral surface charge, relatively small diameter which allow them to rapidly penetrate through mesh like biological barriers such as mucus and mucosal layers (Specification, e.g., pg .16:9 - pg. 17:21, table 1, pg. 65).
Thus, to the extent that the proffered results are contingent on the physicochemical properties of the nanoparticles in the composition, the specification does not show similar results or physicochemical properties for polymer compositions which vary from the disclosed examples.
The specification does not exemplify any other biodegradable polymer apart from PBAE based on 4-amino-1 butanol and 1,4-butanediol diacrylate; hydrophilic polymer apart from than methoxy PEG; ratio of non-conjugated PBAE to methoxy PEG conjugated PBAE in the core apart from 2:3, polymer molecular weights, etc. The specification does not show similar results for a variety of nanoparticle compositions so that one of ordinary skill in the art would be able to determine a trend in the exemplified data which would allow the artisan to reasonably extend the probative value thereof over the full scope of the claimed invention (MPEP 716.02(d), I).
The comparative data is not a comparison with the closest prior art.
The presence of objective evidence of patentability does not mandate a conclusion of patentability in and of itself. Although the record may establish evidence of secondary considerations which are indicia of nonobviousness, the record may also establish such a strong case of obviousness that the objective evidence of nonobviousness is not sufficient to outweigh the evidence of obviousness. See MPEP 716.01(d).
The claimed invention is directed to an immunogenic composition comprising one or more adjuvants and mucus penetrating nanoparticles rather than a method of immunization comprising intratracheal administration.
The record establishes that Hanes teaches compositions comprising mucus penetrating particles and a plasmid DNA which is capable of being recognized as an antigen, i.e., can be considered an immunogenic composition. Thus, Hanes only differs from the disclosed particles used to obtain the proffered results by the addition of a co-encapsulated CpG adjuvant.
The prior art of record is very close to the claimed compositions and the evidence of obviousness is of significant weight. Applicant’s proffered results are based on mucus penetrating particles having the same specific PBAE/PBEAE-PEG blend disclosed by Hanes, WO 2015175545 A1, e.g., pp. 3-5, pg. 46, and example 1, e.g., pp. 54-58), and wherein the core encapsulates nucleic acid (plasmid DNA).
The specification clearly states the amount and ratio of polymers used for the particles are identical to those reported in Mastorakos 2015 and US 20170072064 A1 which is the US publication of the disclosure of the cited Hanes WO reference. See specification, e.g., pg. 19:16-18. The specification further suggests the only difference is that the disclosed particles have nucleic acid based adjuvants co-packaged with the antigen encoding plasmid DNA in contrast to the previous formulations including only plasmid DNA (Specification, e.g., pg. 19:18-20).
The specification suggests mucus penetrating particles (MPP) - like those of Hanes, which do not include an adjuvant cargo - have the same physiochemical properties that render the particles muco-inert and permeable to airway mucus (Specification, e.g., pg. 63:8-28). Thus, the specification suggests the prior art particles lacking an adjuvant cargo will have similar mucus penetrating properties based on the similarity of physiochemical properties which render the particles muco-inert and permeable to airway mucus.
The closest prior art of record is a mucous penetrating particle comprising a plasmid (antigen) but lacking an adjuvant cargo. See Hanes.
Thus, the closest prior art is a mucous penetrating particle having the same exemplified polymer blend composition and coating used to obtain the proffered results. See Hanes.
The comparator composition in the specification is the adjuvant/antigen without a carrier (Examples 3, 4, and 6). The closest prior art (Hanes) is not a mucous impermeable conventional particle, or a naked adjuvant/antigen. Hanes’ particles are mucus penetrating particles based on the same PBAE/PBAE-PEG blend employed in the exemplified mucus penetrating particles.
Since the closest prior art appears to be the same nanoparticle composition which differs only by the absence of nucleic based adjuvant co-packaged with the antigen encoding plasmid DNA, the proffered data does not appear to be a comparison with the closest prior art.
Applicant has not established the results are unexpected.
The burden is on Applicant to establish that the results are unexpected and significant (MPEP 716.02(b). The proffered data is insufficient at least because the claimed invention is not commensurate in scope with the disclosed mucus penetrating particle, and the results are not based on a comparison with the closest prior art as discussed supra.
Further, based on the prior art of record, it is not clear that greater immunity and anti-cancer effect are unexpected results.
Both Hanes and Mastorakos teach the particles offer mucus penetrating properties, i.e., the particles are referred to as mucous penetrating particles (PBAE-MPP), and offer improved particle distribution. For example, Hanes notes the PBAE/ PBAE-PEG based MPPs offer significantly higher distribution in the lung tissues when administered intratracheally relative to conventional particles (Hanes, e.g., example 2, e.g., ¶ spanning pp. 65-66).
Hanes teaches the particles are effective for treating cancer (Hanes, e.g., pg. 35; pg. 47:15-24; pg. 4826-30: cancer treatment of the respiratory tract).
Adjuvants are included in immunogenic compositions to increase immunogenicity of an antigen, promoting potent and persistent immune responses (Hipp, e.g., 0005-0007). CpG oligonucleotides were know antigens and suggested for therapeutic or prophylactic induction of an innate immune response (Hipp, e.g., 0021 and 0235). Therefore, it was expected that including an adjuvant with the antigen plasmid would result in improved immune responses.
Hanes further notes that PEG-PBAE gene vectors resulted in significantly higher transfection compared to PEI and PEG-PLL based particles in vivo (Hanes, e.g., pg. 5:20-32).
Bivas-Benita and Liu suggest pulmonary administration of PEI-DNA nanoparticles and lipid nanocapsules were known to induce higher systemic immunity than intramuscular or subcutaneous administration. For example, Bivas-Benita teaches T-cell responses in the lymph nodes (MLN) of pulmonary immunized mice was 10 fold higher than the response in MLN of IM immunized mice (Bivas-Benita, e.g., pg. 5768, and Fig. 4b). Thus, to the extent that systemic immune response is characterized by lymph nodes (mediastinal LN, see Spec, e.g., pg. 71), the references suggest it was expected that pulmonary administration would result in higher systemic immune response relative to IM as measured in the lymph nodes.
Bivas-Benita teaches pulmonary DNA immunization is an effective strategy to generate protective immunity against respiratory pathogens, but also protects against infections that are initiated at other mucosal sites based on immune responses in the systemic and distant mucosal compartments (Bivas-Benita, e.g., pg. 5773). The proffered results appear to confirm the CTL response shows similar systemic immunity for pulmonary immunization, expected from Bivas-Benita and Liu, using mucus penetrating particles known from the combined teachings of Hanes and Hipp. Since neither Bivas-Benita nor Liu discuss mucus penetrating nanoparticles, it is not clear how these references inform expectations for the systemic immunity difference between mucus penetrating particles administered intratracheally and carrier free adjuvanted plasmid DNA administered IM or ID. However, the proffered results for intratracheal administration of compositions comprising mucus penetrating particles encapsulating an adjuvant and plasmid antigen appear to be the expected improved systemic immunity and distal mucosal site immune response from pulmonary administration based on findings of Bivas-Benita and Liu.
The improved particle distribution in lung and significantly higher transfection offered by the mucus penetrating particles of Hanes indicates the skilled artisan would have expected greater tissue exposure to the encapsulated antigen, and significantly improved expression of the encapsulated antigen plasmid vector, culminating in a greater observed immune response and greater anti-cancer effect.
In other words, since the prior art particles offered mucus penetrating properties resulting in higher tissue distribution and higher transfection efficiency of the encapsulated antigen plasmid, it appears the results proffered by applicant flow naturally from practicing methods of vaccination using mucus penetrating particles suggested by Hanes and Hipp. The mucus penetrating nanoparticles used to obtain the proffered results appear to have the same composition and optimized physicochemical properties as the mucus penetrating nanoparticles in Hanes.
Since the proffered results are not compared to the prior art mucus penetrating particles lacking an adjuvant cargo (Hanes), and since the skilled artisan would have expected greater immune response from pulmonary delivery, and improved mucosal surface penetration, tissue distribution, and transfection of the plasmid encoding the antigen when delivered from the prior art mucus penetrating particles, it cannot be clearly concluded that the proffered results are unexpected. For these additional reasons, the evidence of secondary considerations does not outweigh the evidence of obviousness based on the current record.
Rejections Addressing Applicant’s Amendment
Claim Rejections - 35 USC § 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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.
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 58 and 59 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 pre-AIA the applicant regards as the invention.
There is a lack of antecedent basis for “the free biodegradable polymer not conjugated to the hydrophilic polymer.” Claim 59 includes this limitation since it depends from claim 58.
Separately, there is a lack of antecedent basis for “the blended polymer” in claim 59.
Clarification is required.
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 of this title, 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.
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 25-30, 32-33, 43-49, 51-56 and 58-66 are rejected under 35 U.S.C. 103 as being unpatentable over Hanes, WO 2015175545 A1 (cited on Applicant’s IDS dated 06/16/2023) in view of Hipp, US 20180296663 A1.
Claim 25 has been amended to recite the composition comprises one or more adjuvants and mucus penetrating nanoparticles formed of a biodegradable polymer and a hydrophilic polymer, and wherein > 50% of the biodegradable polymer is conjugated to the hydrophilic polymer.
Hanes teaches compositions comprising nanoparticles for delivery of nucleic acids across biological barriers, comprising a blend of a first biocompatible polymer, and a second hydrophilic, neutrally charged polymer selected from the group consisting of polyethylene glycol, polyethylene oxide, and copolymers thereof, wherein more than 50% of the biocompatible polymer is conjugated to the hydrophilic, neutrally charged polymer, so that the nanoparticle is coated with the hydrophilic, neutrally charged polymer at a density that imparts a near neutral surface charge, and nucleic acids encapsulated within the nanoparticle or are associated with the surface of the nanoparticle (Hanes, e.g., Abstract and claims, e.g., claim 10). The biodegradable polymer is PBAE (Hanes, e.g., examples and claim 11). The biodegradable PBAE is conjugated to methoxy PEG which is a hydrophilic polymer (Hanes, e.g., pp. 19-20 and pg. 41, and example 1, e.g., pg. 55). The plasmid is complexed with un-conjugated PBAE and the unconjugated PBAE/plasmid is blended with the PBAE-methoxy PEG conjugate to form the core of biodegradable polymer encapsulating a nucleic acid encoding a polypeptide (antigen) coated with a hydrophilic methoxy PEG polymer (Hanes, e.g., pg. 41, example 1, pp. 55-56). This arrangement offers improved colloidal stability and enhanced penetration through biological barriers, e.g., airway mucus (Hanes, e.g., pp. 3-4).
Hydrodynamic diameter is less than 100 nm with a near neutral surface charge (Hanes, e.g., pp. 3-5, pg. 46, and pg. 58).
Hanes demonstrates effectiveness of nanoparticles containing a plasmid DNA. Nanoparticles carried plasmid DNA encoding for green fluorescent protein (GFP) driven by a β-actin promotor operably linked to the nucleic acid sequence encoding the protein (Hanes, e.g., pg. 66: 13-24 and pg. 67).
Hanes teaches nanoparticle compositions useful as nucleic acid carrying nanoparticle gene carriers and nanoparticle vectors comprising a plasmid DNA which encodes a polypeptide (Hanes, e.g., pg. 23:25-29, and pg. 66: 13-24 and pg. 67).
Hanes teaches nanoparticle compositions useful for delivering nucleic acid molecules that act as effectors, inhibitors, modulators, and stimulators of a specific activity in a nanoparticle which allow the gene vectors to rapidly penetrate mucus (Hanes, e.g., pg. 48) thereby enabling delivery across the mucosa linings throughout the body (Hanes, e.g., pg. 39). The nanoparticles are taught as mucus penetrating particles or PBAE-MPP, and may be useful for mucus penetration, and increased expression e.g., in the lungs (Hanes, e.g., Abstract, pg. 17-18, pg. 19, pg. 36, pg. 59).
Although Hanes teaches compositions comprising nanoparticles comprising a plasmid DNA encoding a polypeptide which is capable of being recognized as an antigen, Hanes does not expressly characterize the plasmid DNA as an antigen. Hanes does not expressly teach the composition further comprising an adjuvant.
Hipp teaches vaccine compositions comprising an antigen (Hipp, e.g., Abstract, claims, and 0048, 0025), wherein the antigen is a plasmid DNA encoding a desired antigen (Hipp, e.g., 0271), a nanoparticle carrier (Hipp, e.g., 0245-0252, 0484 and claim 15), and an adjuvant (Hipp, e.g., claim 1, and 0007 and 0046-0047). Adjuvants stimulate the immune response and include oligonucleotides comprising unmethylated CpG motifs (Hipp, e.g., 0235 and 0477) which are ligands for TLR9 (Hipp, e.g., 0158).
Hipp teaches the adjuvant may be formulated with the nucleic acid encoding the antigen or separately (Hipp, e.g., 0078-0080).
Hipp teaches polymeric lipid nanoparticles (Hipp, e.g., 0247-0248) but does not teach nanoparticles comprising a blend of biodegradable hydrophobic polymer and hydrophilic polymer conjugated to biodegradable hydrophobic polymer as claimed.
Starting from Hanes:
It would have been obvious before the effective filing date of the presently claimed invention to modify compositions comprising a nanoparticle carrier for plasmid DNA as known from Hanes using the teachings of Hipp to improve the nanoparticle compositions for vaccine administration in the same way with a reasonable expectation of success. Since Hanes teaches nanoparticle compositions offering improved mucus penetration and biological barrier penetration useful for delivery of plasmid DNA, the skilled artisan would have been motivated to use Hanes’ nanoparticle delivery compositions for delivery of plasmid DNA encoding polypeptide antigens and adjuvants using techniques known from Hipp. The skilled artisan would have had a reasonable expectation of success because both references teach delivery systems effective to deliver plasmid DNA.
Starting from Hipp:
It would have been obvious before the effective filing date of the presently claimed invention to modify carrier compositions suggested by Hipp using polymer nanoparticle techniques known from Hanes to improve Hipp’s compositions in the same way suggested by Hanes with a reasonable expectation of success. The skilled artisan would have been motivated to use nanoparticle techniques known from Hanes to improve stability of plasmid DNA antigen vectors for rapid mucus penetration and enhanced biological barrier penetration reported by Hanes. The skilled artisan would have had a reasonable expectation of success because both references teach delivery systems effective to deliver plasmid DNA.
Hipp teaches the adjuvant may be formulated with the nucleic acid encoding the antigen or separately (Hipp, e.g., 0078-0080). Thus, the skilled artisan would have found it obvious to formulate the adjuvant in the same nanoparticles which contain the plasmid DNA encoding the antigen or separately from the nanoparticles which contain the plasmid DNA encoding the antigen with a reasonable expectation of success.
Applicable to claims 45-49 and 51: Hanes teaches a plasmid DNA containing a β-actin promotor operably linked to the nucleic acid sequence encoding the protein for long term transgene experssion (Hanes, e.g., pg. 66: 13-24 and pg. 67).
Applicable to claim 58: Hanes teaches free biodegradable polymer ratio unconjugated polymer to conjugated polymer is between 0.5 and 1 (Hanes, e.g., claim 17).
Applicable to claim 59: Hanes teaches a PBAE to plasmid DNA ratio of up to 100 (Hanes, e.g., claim 5 and claim 19).
Applicable to claim 63: Hanes teaches PBAE having a molecular weight in the claimed range, e.g., 4-7 kDa (Hanes, e.g., claim 12, e.g., pg. 8721, Fig. 1).
Applicable to claims 64-65: PEG is a polyalkylene oxide and polyethylene glycol and Mastorakos teaches PEG having a molecular weight between 1000 and 10000 Daltons, e.g., 5000 Da (Hanes, e.g., claims 13 and 14). This molecular weight is within the claimed range.
Applicable to claim 66: Hipp teaches compositions further comprising a ligand which functions to target dendritic cells (Hipp, e.g., 0151). Additional ligand adjuvants are taught at Hipp, e.g., 0158-0160, 0239-0242. Cytokine adjuvants, e.g., tumor necrosis factor, are taught at Hipp, e.g., 0250.
Accordingly, the subject matter of claims 25-30, 32-33, 43-49, 51-56 and 58-66 would have been prima facie obvious before the effective filing date of the presently claimed invention, absent evidence to the contrary.
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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to WILLIAM A CRAIGO whose telephone number is (571)270-1347. The examiner can normally be reached on Monday - Friday, 9am - 6pm, PDT.
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/WILLIAM CRAIGO/Examiner, Art Unit 1615
/SUSAN T TRAN/Primary Examiner, Art Unit 1615
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