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
Claim 25, 27, 33, 35, 38, 40-43, and 45 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II and III, there being no allowable generic or linking claim. Election was made with traverse in the reply filed on 9/11/2024. However, as stated in the CTNF of 10/15/2024 and 6/11/2025, the requirement is still deemed proper and is therefore made FINAL.
Status of Claims
Cancelled: 5, 6, 8, 10, 11, 14-21, 23, 24, 26, 28-32, 34, 36, 37, 39, 44, 46-49
Withdrawn: 13, 22, 25, 27, 33, 35, 38, 40-43, 45
Examined Herein: 1-4, 7, 9, 12, 50, 51
Priority
Priority to GB1818517.3 filed on 11/13/2018 and PCT/GB2019/053218 filed on 11/13/2019 is
acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/27/2021 and 7/26/2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure
statement is being considered by the examiner.
Drawings
The drawings filed on 5/13/2021 are accepted.
Withdrawn Rejections
The objection of claim 4 is hereby withdrawn in view of Applicant’s amendment to claim 4 which replaces the term “absorbed” with “adsorbed.”
The rejection of claims 1-3 and 12 under 35 U.S.C. 103 over Galli and Jayakrishnan is hereby withdrawn in view of Applicant’s substantive amendments to claim 1.
The rejection of claims 1-3, 12, and 51 under 35 U.S.C. 103 over Galli, Jayakrishnan, and Lavik is hereby withdrawn in view of Applicant’s substantive amendments to claim 1.
The rejection of claims 1-4, 7, 12, and 50 under 35 U.S.C. 103 over Galli, Jayakrishnan, and Trottein is hereby withdrawn in view of Applicant’s substantive amendments to claim 1.
The rejection of claims 1-3, 9, and 12 under 35 U.S.C. 103 over Galli, Jayakrishnan, and Jon is hereby withdrawn in view of Applicant’s substantive amendments to claim 1.
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.
Claims 1-4, 7, 12, and 50 are rejected under 35 U.S.C. 103 as being unpatentable over Trottein (US 2015/0374734 A1, Published 12/31/2015), in view of Hwang (US 2015/0374850 A1, Published 12/31/2015).
With respect to claim 1, Trottein discloses a nanoparticle comprising a polymer (PLGA), a-Galactosylceramide (α-GalCer) and a coating, wherein the α-GalCer is incorporated within the polymer, and the nanoparticle is coated (e.g., with a polymeric coating). [Trottein, 0123, 0124, 0127, 0136, 0188]
With respect to claim 2, Trottein discloses that the polymer comprises a synthetic polymer, PLGA. [Trottein, 0116, 0127, 0188]
With respect to claim 4, Trottein discloses that the nanoparticle further comprises an antigen (or antigenic determinant) that may be physically coupled to the surface of the nanoparticle via non-covalent linkage, including electrostatic interactions. [Trottein, 0116, 0127, 0136, 0188]
With respect to claim 7, Trottein discloses that the antigen may be a protein. [Trottein, 0148] Trottein further discloses that the antigen may be derived from pneumococcus (aka S. pneumoniae). [Trottein, 0151]
With respect to claim 12, Trottein discloses that the nanoparticle may be in a buffered or saline solution. [Trottein, 0159]
With respect to claim 50, Trottein discloses that the nanoparticle further comprises an antigen (or antigenic determinant) conjugated to a surface of the nanoparticle. [Trottein, 0116, 0127, 0136, 0188]
Moreover, Trottein discloses that the nanoparticles may also be functionalized or coated to produce a desirable physical characteristic such as solubility, biocompatibility, and for facilitating chemical linkages with other biomolecules. For example, the surface of the nanoparticles can be functionalized by incorporating one or more polymers such as silane, dextran or PEG or their derivatives. [Trottein, 0123, 0124]
Trottein does not disclose that the nanoparticle comprises chitosan HCl coated on the surface.
However, with respect to claims 1 and 2, Hwang discloses a nanocomposite having a particle size of 10-500 nm where chitosan is coated on the surface. [Hwang, 0064] Hwang further discloses that, in terms of solubilization, the chitosan is preferably water-soluble chitosan, water-insoluble chitosan, or chitosan derivatives with modified molecular structures, preferably water-soluble chitosan including chitosan HCl. [Hwang, 0047-0048] Hwang discloses that the water-soluble chitosan is advantageous in that it can eliminate bacteria or other impurities during the process of injection preparation. [Hwang, 0048]
Modifying the nanoparticle disclosed by Trottein by coating it with chitosan HCl results in the nanoparticle of claims 1 and 2.
It would be obvious to one ordinary skill in the art to modify the nanoparticle disclosed by Trottein by coating it with chitosan HCl and have a reasonable expectation of success. Trottein discloses a nanoparticle comprising a coating. Trottein discloses that the coating is capable of producing a desirable physical characteristic and facilitate chemical linkages with other biomolecules, and in one embodiment, is polymeric. Hwang discloses a nanoparticle coated with chitosan. Hwang further discloses that the chitosan is preferably water-soluble, including chitosan HCl. Accordingly, the combined teachings of Trottein and Hwang reasonably suggest that a polymeric coating like chitosan HCl may coat the nanoparticle disclosed by Trottein. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. MPEP 2144(II). In the present case, Hwang discloses that chitosan is a very safe cationic polysaccharide and water-soluble chitosan (e.g., chitosan HCl) is advantageous because it can eliminate bacteria or other impurities. [Hwang, 0046, 0048] Therefore, one would have been motivated by the expectation that coating the nanoparticle with chitosan would yield a biocompatible nanoparticle with desirable solubility characteristics and advantageously eliminate bacteria or other impurities.
Claims 1-4, 7, 9, 12, and 50 rejected under 35 U.S.C. 103 as being unpatentable over Trottein and Hwang, as applied to claims 1-4, 7, 12, and 50 above, and further in view of Jon (US 2008/0268063 A1, Published 10/30/2008).
With respect to claim 1, Trottein and Hwang disclose the teachings above.
With respect to claim 9, Trottein discloses that the nanoparticles may be combined with one or more excipients. [Trottein, 0159]
The limitation "wherein the dry powder format is produced by spray drying the nanoparticles" recites a product-by-process limitation, which is unpatentable even if the prior art product was made by a different process. MPEP 2113(I). The limitation "suitable for inhalation" recites an intended use but does not impart a structural difference between the claimed invention and the prior art. Therefore, this limitation is not patentably distinguishable from the prior art. MPEP 2111.04.
Trottein and Hwang do not disclose that the nanoparticle is in a dry powder format.
However, with respect to claim 9, Jon discloses a nanoparticle comprising a polymer core encapsulating a predetermined amount of the active agent; and a mucoadhesive coating disposed about the core to form a coated particle. [Jon, 0009-0010, 0043] Jon discloses that a variety of methods of making particles in which active agents are encapsulated are well known to those skilled in the art, including that particles may be prepared by spray drying. [Jon, 0051] Jon further discloses that solid dosage forms for administration of the composition include powders and that powders and sprays can contain, in addition to the inventive particles of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures thereof. [Jon, 0081, 0083]
Modifying the nanoparticle disclosed by Trottein and Hwang by formulating it as a powder results in the nanoparticle of claim 9.
It would be obvious to one of ordinary skill in the art to modify the nanoparticle disclosed by Trottein and Hwang by formulating it as a powder and have a reasonable expectation of success. Trottein and Hwang disclose a nanoparticle comprising a chitosan HCl coating on the surface thereof, a polymer, PLGA, and an agent, α-GalCer, encapsulated therein. Jon discloses a nanoparticle comprising a polymer core, an active agent encapsulated therein, and a mucoadhesive (e.g., chitosan) coating on the surface. Jon further discloses that such a nanoparticle may be formulated into a powder. Accordingly, the combined teachings of Trottein, Hwang, and Jon reasonably suggest that the nanoparticle disclosed by Trottein and Hwang may be formulated into a powder format. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. MPEP 2144(II). In the present case, Trottein further discloses that the nanoparticle composition may be formulated for administration by inhalation. [Trottein, 0160] Jon discloses that the nanoparticle may be formulated for administration by inhalation, specifically as sprays. [Jon, 0080] Jon further discloses that the sprays contain dry powders including talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder. [Jon, 0081] Therefore, one would have been motivated by the expectation that formulating the nanoparticle disclosed by Trottein and Hwang into dry powder format would make it suitable for inhalation.
Claims 1-4, 7, 12, 50, and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Trottein and Hwang, as applied to claims 1-4, 7, 12, and 50 above, and further in view of Lavik (US 2013/0316010 A1, Published 11/28/2013).
With respect to claims 1 and 2, Trottein and Hwang disclose the teachings above.
Trottein and Hwang do not disclose that the PLGA comprises lactic acid and glycolic acid in a ratio of 75:25.
However, with respect to claim 51, Lavik discloses a microparticle composition comprising PLGA with a lactic acid to glycolic acid to a ratio of about 75:25 and an active agent encapsulated therein. [Lavik, 0021, 0017] Lavik discloses that the microparticle is optimized for an agent to be delivered, so that the hydrophobicity or hydrophilicity of the polymer and charge of the polymer maximizes loading of the agent, and the selection and molecular weight of the polymers maximize release of an effective amount of the active agent for the desired period of time. [Lavik, 0013] The microparticle compositions release an effective amount of the active agent for a period greater than 14 days in vivo to greater than 120 days in vivo. The desired amount and duration of release is dependent upon several factors including the disease or disorder to be treated, the active agent to be delivered, and the frequency of administration. [Lavik, 0015]
Modifying the nanoparticle disclosed by Trottein and Hwang so that the PLGA has a lactic acid to glycolic acid ratio of about 75:25 results in the nanoparticle of claim 51.
It would be obvious to one of ordinary skill in the art to modify the nanoparticle disclosed by Trottein and Hwang so that the PLGA has a lactic acid to glycolic acid ratio of about 75:25 and have a reasonable expectation of success. Trottein and Hwang disclose a nanoparticle comprising PLGA and α-GalCer encapsulated therein. Lavik discloses a microparticle comprising PLGA with a lactic acid to glycolic acid ratio of about 75:25 and an active agent encapsulated therein. Accordingly, the combined teachings of Trottein, Hwang, and Lavik reasonably suggest that the nanoparticle disclosed by Trottein and Hwang may have a lactic acid to glycolic acid ratio of about 75:25. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. MPEP 2144(II). In the present case, Lavik discloses that the microparticles comprising PLGA having a lactic acid to glycolic acid ratio of about 75:25 are optimized for the agent encapsulated therein to be delivered, so that the hydrophobicity or hydrophilicity of the polymer and charge of the polymer maximizes loading of the agent, and the selection and molecular weight of the polymers maximize release of an effective amount of the active agent for the desired period of time. [Lavik, 0013, 0020] Therefore, one would have been motivated by the expectation that modifying PLGA in the nanoparticle disclosed by Trottein and Hwang so that it has a lactic acid to glycolic acid ratio of about 75:25 would maximize loading, delivery, and release of the α-GalCer encapsulated.
Response to Arguments
Applicant's arguments filed 6/26/2026 have been fully considered but they are not persuasive.
Applicant's arguments with respect to claims 1-3 and 12 over Galli and Jayakrishnan [Remarks 6/26/2026, Page 8 – Page 11, Paragraph 2] have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any matter specifically challenged in the argument.
Applicant asserts, “Applicant respectfully submits that it is completely inappropriate to use LPS to refute the superiority of HCl chitosan in this experiment. Rather, focus should be paid to the evidence that the use of HCl chitosan is clearly superior to the negative control (media) and a large number of the other chitosan-based coatings (LMW, CMC, TMC and oligomer), especially given that such an effect is neither disclosed nor anticipated by the cited prior art.” [Remarks 6/26/2026, Page 12, Paragraph 3 - Page 13, Paragraph 1]
Applicant’s arguments are not persuasive because the Office did not use LPS to refute the superiority of HCl chitosan and the Office’s comments referencing LPS were appropriate.
The submission of objective evidence of patentability does not mandate a conclusion of patentability in and of itself. In re Chupp, 816 F.2d 643, 2 USPQ2d 1437 (Fed. Cir. 1987). Facts established by rebuttal evidence must be evaluated along with the facts on which the conclusion of a prima facie case was reached, not against the conclusion itself. In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990). In other words, each piece of rebuttal evidence should not be evaluated for its ability to knockdown the prima facie case. All of the competent rebuttal evidence taken as a whole should be weighed against the evidence supporting the prima facie case. In re Piasecki, 745 F.2d 1468, 1472, 223 USPQ 785, 788 (Fed. Cir. 1984). 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. MPEP 716.01(d).
Therefore, it is not inappropriate for the Office to consider the totality of the evidence, including the positive control LPS, because all evidence must be weighed against the evidence supporting the prima facie case. The fact that LPS is a positive control and provides “evidence of what an immunological response would look like in this current experimental setup” is precisely what necessitates its consideration. The relevant inquiry is not whether chitosan HCl is superior to LPS or vice versa. Rather, the relevant inquiry is whether the result obtained with chitosan HCl differs from what a POSITA would have expected and the positive control is relevant to that inquiry.
Furthermore, the Office did focus on evidence comparing HCl chitosan to the negative control (media) and other chitosan-based coatings (LMW, CMC, TMC, and oligomer). The CTNF of 4/1/2026 states on Page 14, “Figures 19, 20, and 26 of the specification demonstrate that multiple adjuvants, including other chitosan derivatives, achieve a similar increase in immunogenicity compared to a control comprising no chitosan.” However, the Office’s conclusion remains unchanged. Applicant’s data reflects a difference in degree rather than in kind. This conclusion is based on the evidence comparing HCl chitosan to the negative control (media) and other chitosan-based coatings, not upon the LPS data.
With respect to Applicant’s allegations of unexpected results, Applicant seemingly makes three principal arguments: [Remarks 6/26/2026, Page 11, Paragraph 3 – Page 13]
(1) Chitosan HCl surprisingly improves the immunogenic properties of vaccines and advantageously enhances the immunogenic response
(2) Chitosan HCl is clearly superior to a large number of the other chitosan-based coatings
(3) The claimed nanoparticle surprisingly led to a greater immune response in mice and improved the survival of mice infected with Streptococcus pneumonia
With respect to principal argument (1), Applicant asserts “Applicant respectfully submits that there is absolutely nothing in any of the cited prior art documents that would suggest that a coating of HCl chitosan can enhance the immunogenic function of the resulting nanoparticles/vaccine.” [Remarks 6/26/2026, Page 13, Paragraph 3]
The immunostimulatory properties of chitosan HCI were already known in the art, and the effects demonstrated by the Applicant were consistent with a POSITA’s understanding at the time of filing the instant invention. In fact, Galli contemplates the effects of most of the adjuvants disclosing that chitosan, chitosan derivatives, and LPS are all adjuvants that function as immunoregulatory agents. [Galli, 0095, 0105, 0114] Additionally, Singh (US 2005/0281843 A1, Published 12/22/2005) discloses that the mucosal delivery of bioadhesives, including mucoadhesive and mucoadhesive derivatives, in combination with an antigen enhances the immunogenicity of the antigen co-administered therewith. [Singh, 0008] Chitosan HCI is a known mucoadhesive. Accordingly, one of ordinary skill in the art would have reasonably expected chitosan HCI to enhance the immunogenicity of an antigen.
Applicant asserts, “Furthermore, it would not be obvious to a person skilled in the art to incorporate a HCl chitosan coating based on the common general knowledge at that time, which the Applicant summarizes in the application as filed: " ... most literature references use non-water-soluble chitosan which is dissolved in acetic acid." See page 15, lines 13-14 of the specification as filed.” [Remarks 6/26/2026, Page 13, Paragraph 3]
Applicant’s summary in the application as filed reflects their own characterization of the common general knowledge at that time. This does not make the characterization accurate. For example, Hwang (cited above) discloses coating the surface of a nanoparticle with chitosan. [Hwang, 0064] Hwang discloses that, in terms of solubilization of chitosan, water-soluble chitosan is preferred over water-insoluble chitosan and chitosan derivatives with modified molecular structures. Hwang discloses that the water-soluble chitosan may be chitosan HCl and that water-soluble chitosan is advantageous in that it can eliminate bacteria or other impurities. [Hwang, 0047-0048]
Therefore, it would have been obvious to a POSITA to incorporate a chitosan coating, and more specifically chitosan HCl coating, because the art expresses a preference for water-soluble chitosan over water-insoluble chitosan and chitosan derivatives with modified molecular structures, and because water-soluble chitosan can advantageously eliminate bacteria or other impurities.
With respect to principal argument (2), Applicant asserts “Nanoparticles coated with HCI chitosan showed one of the highest CD86 and CD40 expression of the chitosan based adjuvants,” and “… the use of HCl chitosan is clearly superior to the negative control (media) and a large number of the other chitosan-based coatings (LMW, CMC, TMC and oligomer)…” [Remarks 6/26/2026, Page 12, Paragraph 2; Page 13, Paragraph 1]
Applicant relies on Figures 19, 20, and 26 to support their conclusion that chitosan HCl is superior to a large number (n=4) of the other chitosan-based coatings.
In Figures 19 and 20, Applicant measures the median fluorescence intensity (MFI) when Ref+chitosan (Fig. 19) or 75:25+chitosan (Fig. 20) with PspA nanoparticles were incubated with JAWS II cells and stained for A. CD40 and B. CD86, respectively, to determine the immunogenicity of each polymer nanoparticle. Applicant compares chitosan HCl with six other chitosan-based coatings: ow molecular weight (LMW), trimethylchitosan (TMC), carboxymethylchitosan (CMC), oligomer, glutamate, and glycol. The comparison is summarized below:
• Figure 19A: chitosan HCl’s performance is inferior to chitosan glycol
• Figure 19B: chitosan HCl’s performance is superior to all other chitosan-based coatings
• Figure 20A: chitosan HCl’s performance is inferior to chitosan glycol and comparable with CMC and oligomer chitosan
• Figure 20B: chitosan HCl’s performance is inferior to chitosan glycol and comparable with LMW
Moreover, the specification states, “As shown in FIGS. 19 and 20, the ref and 75:25 polymers exhibited similar patterns of upregulation, with the HCl and glycol having the highest MEI for CD40, and HCl and LMW having the highest CD86 expression.” [Specification, Page 23, Line 5-8]
In Figure 26, Applicant measures the proportion of CD3/CD4-positive cells which were measured in the splenocyte population by staining with anti-CD3 and CD4 antibodies and gating for the positive populations. Applicant compares chitosan HCl with eight other chitosan-based coatings LMW, TMC, CMC, Oligomer, Glutamate, Glycol, chitosan aspartate (ASP), and chitosan-g-acrylamidoglycolic acid (AGA). The comparison is summarized below:
• Figure 26: chitosan HCl’s performance is inferior to LMW
Moreover, the specification states “As shown in FIG. 26, the data showed greater CD3/CD4 positive proportions in the HCl, LMW and TMC chitosan groups, indicating T cell proliferation.” [Specification, Page 25, Line 2-4]
The specification additionally asserts the following:
• The toxicity of Ref+chitosan with PspA & 75:25+chitosan with PspA were evaluated again using 7AAD. The toxicity reflects the pattern shown by the immunogenicity of the Ref chitosan formulations, with the HCl and glycol formulations exhibiting the highest MFI. [Specification, Page 22, Line 16-18]]
• The 7AAD MFI suggested a chitosan concentration dependent pattern, with highest ASP concentration exhibiting the highest 7AAD MFI. [Specification, Page 26, Line 10-12]
• As shown in FIG. 25, the lower CFSE MFI signal of the splenocytes indicated proliferation, but there may all chitosan groups exhibited similar results. [Specification, Page 24, Line 20-22]
• As shown in FIG. 27, cytokine release into the cell culture medium was also measured but did not show any consistent pattern. [Specification, Page 25, Line, 6-7]
Accordingly, in view of Figures 19, 20, and 26, while there is one (out of five) instance where chitosan HCl’s performance is superior to all other chitosan-based coatings, there are also four instances where other chitosan-based coatings, including LMW, chitosan glycol, CMC, and oligomer, outperform or perform comparably to chitosan HCl. In addition to the data, throughout the experimental section of the specification that chitosan HCl’s performance is described as comparable to other chitosan-based coatings. Therefore, Applicant’s conclusion that chitosan HCl is superior to a large number of other chitosan-based coatings is contradicted by the evidence provided.
With respect to principal argument (3), Applicant asserts, “the present inventors have shown that the supplementation of a vaccine comprising the claimed nanoparticle led to a greater immune response in mice (due to the higher anti-Psp antibody titer) and improved the survival of mice infected with Streptococcus pneumonia, as illustrated in Figure 31.” [Remarks 6/26/2026, Page 12, Paragraph 1]
Applicant’s arguments are not persuasive because Figure 31 compares the claimed nanoparticle with a nanoparticle without α-GalCer and concludes that the claimed nanoparticle led to a greater immune response. The evidence must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. MPEP 716.02(e). The closest prior art, Trottein, discloses a nanoparticle comprising α-GalCer encapsulated within. Accordingly, comparing the claimed nanoparticle against a nanoparticle without α-GalCer is ineffective to rebut the prima facie case of record.
Applicant asserts the following:
• “Specifically, Lavik also fails to disclose or suggest a nanoparticle comprising a polymer, a-Galactosylceramide and chitosan hydrochloride, wherein the a-Galactosylceramide is incorporated within the polymer, and the nanoparticle is coated with the chitosan hydrochloride.” [Remarks, Page 14, Paragraph 2]
• “Specifically, Trottein also fails to disclose or suggest a nanoparticle comprising a polymer, a-Galactosylceramide and chitosan hydrochloride, wherein the a-Galactosylceramide is incorporated within the polymer, and the nanoparticle is coated with the chitosan hydrochloride.” [Remarks, Page 15, Paragraph 2]
• “Specifically, Jon also fails to disclose or suggest a nanoparticle comprising a polymer, a-Galactosylceramide and chitosan hydrochloride, wherein the aGalactosylceramide is incorporated within the polymer, and the nanoparticle is coated with the chitosan hydrochloride.” [Remarks, Page 16, Paragraph 2]
One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. MPEP 2145(IV). The rejections of record are based on the combined teachings of Trottein and Hwang; Trottein, Hwang, and Lavik; or Trottein, Hwang, and Jon. Accordingly, attacking each reference individually fails to overcome the rejections of record, as none of the rejections of record are made over Lavik, Trottein, or Jon alone.
Applicant asserts “Lavik discloses microparticles comprising PLGA including a range of lactic acid to glycolic acid ratios of about 50:50 to 75 :25 which are specific for addressing release kinetics of the encapsulated drug from the microparticles. However, Lavik provides no teaching that the various polymer ratios are relevant or applicable to multicomponent immunological nanoparticle systems such as that of the claimed embodiments.” [Remarks, Page 14, Paragraph 3]
Applicant’s assertion is not persuasive because Lavik’s teachings regarding PLGA and its respective ratios are directly relevant to the nanoparticle disclosed by Trottein and Hwang. The nanoparticle disclosed by Trottein comprises PLGA, the same polymer whose lactic acid-to-glycolic acid ratio Lavik characterizes, and further comprises an agent encapsulated within the polymer, α-GalCer. Lavik discloses that the microparticle is optimized for an agent to be delivered such that the hydrophobicity or hydrophilicity of the polymer and the charge of the polymer maximizes loading of the agent, and the selection and molecular weight of the polymers maximize release of an effective amount of the active agent for the desired period of time. [Lavik, 0013] Therefore, Lavik’s teaching on how the lactic acid-to-glycolic acid ratio of PLGA affects loading of an encapsulated agent is directly applicable to a nanoparticle comprising PLGA with an encapsulated agent, which is precisely what the claimed nanoparticle and the nanoparticle disclosed by Trottein and Hwang are.
Furthermore, the reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. MPEP 2144(IV). A POSITA need not consider whether the polymer ratios are applicable to multi-component immunological nanoparticle systems in order to rely on Lavik.
Applicant asserts, “However, Trottein does not disclose or suggest a chitosan hydrochloride coating which imparts a positive zeta potential and enables antigen association via electrostatic adsorption or van de Waals interactions. Trottein also does not disclose or suggest a chitosan hydrochloride coating of its nanoparticles or provide any suggestion or reason for the skilled person to modify its nanoparticles in this way.” [Remarks, Page 15, Paragraph 3]
Trottein expressly discloses that the surface of the nanoparticles may also be functionalized or coated to produce a desirable physical characteristic such as solubility, biocompatibility, and for facilitating chemical linkages with other biomolecules. [Trottein, 0123] Trottein further discloses that the surface may be functionalized with polymers such as silane, dextran, or PEG, or derivatives thereof. [Trottein, 0124] Therefore, Trottein expressly contemplates selecting a polymeric surface coating and expressly identifies solubility and the association of biomolecules as reasons for doing so.
Applicant asserts “Jon discloses a nanoparticle comprising a synthetic polymer, insulin and chitosan and spray drying of the nanoparticles resulting in a dry powder for administration.” [Remarks, Page 16, Paragraph 3]
Jon discloses the nanoparticle described by Applicant in a specific embodiment. However, Jon’s disclosure is drawn to a composition comprising a polymer core encapsulating a predetermined amount of the active agent; and a mucoadhesive coating disposed about the core to form a coated particle. [Jon, Claim 1] Jon explicitly cautions against limiting the disclosure to examples and discloses that the claims indicate the true scope and spirit of the invention. [Jon, 0144]
Applicant asserts, “However, Jon does not disclose the specific nanoparticle components of amended claim 1 and provides no disclosure or suggestion that the nanoparticles would be suitable for spray drying or that the process would result in an active formulation suitable for use. The skilled person would be aware that even small differences in formulations can result in incompatibility with pharmaceutical processes. Therefore, it would not have been obvious to the skilled person in view of Jon to formulate the nanoparticles into a dry powder format by spray drying due to the differences in nanoparticle components between Jon and the claimed embodiments.” [Remarks, Page 16, Paragraph 3]
Jon’s disclosure is drawn to a composition comprising a polymer core encapsulating a predetermined amount of the active agent; and a mucoadhesive coating disposed about the core to form a coated particle. [Jon, Claim 1] Jon discloses that a variety of methods of making particles in which active agents are encapsulated are well known to those skilled in the art, including that particles may be prepared by spray drying. [Jon, 0051] Jon further discloses that solid dosage forms for administration of the composition include powders and that powders and sprays can contain, in addition to the inventive particles of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures thereof. [Jon, 0081, 0083]
The nanoparticle disclosed by Trottein and Hwang likewise comprises a polymer having an agent encapsulated therein and a mucoadhesive (chitosan HCl) coating on the surface thereof. In these respects, the particle architectures are the same. Accordingly, because Jon discloses that particles having this architecture may be formulated as powders and prepared by spray drying, it is reasonable to suggest that the nanoparticle disclosed by Trottein and Hwang may be formulated as powders and prepared by spray drying.
In any event, Applicant provides no evidence that any difference in components would render the nanoparticle incompatible with spray drying, and arguments presented by applicant cannot take the place of evidence in the record. MPEP 2145(I).
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/K.A.C./Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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