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 .
DETAILED ACTION
The text of those sections of Title 35, U.S. Code not included in this action can be found
in a prior Office action.
This Action is in response to the papers filed on December 19, 2025. Pursuant to the amendment filed on December 19, 2025, claims 1, 6-7, 44, 64, 75-76, 81, 85-86, 93, 113, 123, 152, 154, 161, 181, 221, 225, and 230 are currently pending of which claims 1, 6, 44, 86, 93, 123, 154, 161, and 225 are currently amended. No claims have been amended. No claims have been cancelled.
Claims 1, 6, 7, 44, 64, 75, 76, 81, 85, 154, 161, 181, 221, and 225, were previously withdrawn in the Office Action dated August 15, 2024. Claims 1, 6, and 154 have been amended and requested to be rejoined to the pending examined claims of Group III. As stated in the Restriction Requirement filed on May 16, 2024, a search and examination beyond the elected invention will impose a serious burden on the examiner. Despite the amended claims matching some of the limitations of Group III, the claims remain directed to different statutory categories, e.g. compositions and methods, and therefore the search burden remains, and moreover the lack of unity remains as described previously. The restriction requirement between Groups I-IV was previously made FINAL.
Therefore, claims 86, 93, 113, 123, 152, and 230 are currently under examination to which the following grounds of rejection are applicable.
Response to Arguments
Withdrawn Objections/Rejections in response to Applicants’ arguments or amendments:
Claim Rejections - 35 USC § 101
In view of Applicants’ amendment to the claims dated December 19, 2025, wherein claims 1, 6, 44, 86, 93, 123, 154, 161, and 225 have been amended, the rejection to claim 86 rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural product without significantly more, has been withdrawn.
The withdrawn rejection is in view of the amendment to claim 86 now reciting the limitation, “said antigen and adjuvant are not normally associated with said anucleate cell-derived vesicle in nature,”. Therefore, the “anucleate cell-derived vesicle” is not considered a natural product in view of this limitation.
Drawings
In view of Applicants’ amendment to the Drawings filed on December 19, 2025, wherein Figure 4 has been amended, the objection to Figure has been withdrawn.
Claim Rejections - 35 USC § 112
In view of Applicants’ amendment to the claims filed on December 19, 2025, wherein claims 86 and 93 have been amended, the rejection to claims 86 and 93 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, have been withdrawn.
Claims 86 and 93 have been amended to overcome the indefiniteness issues.
Applicants’ arguments are moot in view of the withdrawn rejection. A response to any argument pertaining to a new or maintained rejection can be found below.
Claim Rejections - 35 USC § 103
In view of Applicants’ amendment to the claims filed on December 19, 2025, wherein claims 86, 93, and 123 have been amended, the rejection to claims 86, 93, 113, 123, 152, and 230 rejected under 35 U.S.C. 103 as being unpatentable over Huang (US-8329161-B2; citations from US Pub. 2009/0274630-A1) in view of Gilbert et al. (US Pub. 2019/0382796A1) and Beleznay et al. (Biochemistry 32.12 (1993): 3146-3152), have been withdrawn.
The withdrawn rejections are in view of the amendments to claim 86 wherein the anucleate cell derived vesicles have both reduced ATP production and increased surface phosphatidylserine levels for which the employed prior art reference of Beleznay teaches reduced ATP production for RBC derived vesicles in comparison to intact RBC, and further describes the lipid composition between both groups as being similar.
Applicants’ arguments are moot in view of the withdrawn rejection. A response to any argument pertaining to a new or maintained rejection can be found below.
New Grounds of Rejection
Claim Objections
Claim 86 is objected to because after the amendment to claim 86 filed on December 19, 2025, the claim now ends with a comma followed by a period. Appropriate correction is required.
Claim Rejections - 35 USC § 112
Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 86 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 86 has been amended to now recite, “wherein the antigen is a nucleic acid, peptide or polypeptide and said antigen and adjuvant are not normally associated with said anucleate cell-derived vesicle in nature,”. In Remarks filed on December 19, 2025, support for the amendment is described as “Specifying that the antigen and adjuvant are not associated with said anucleate cell-derived vesicle in nature. Support can at least be found in paragraph [0148] of the application as published.” The cited section, paragraph 0148 states:
“The term "heterologous" as it relates to amino acid sequences such as peptide sequences and polypeptide sequences, denotes sequences that are not normally joined together, and/or are not normally associated with a particular cell. Thus, a "heterologous" region of a peptide sequence is a segment of amino acids within or attached to another amino acid molecule that is not found in association with the other molecule in nature. For example, a heterologous region of a peptide construct could include the amino acid sequence of the peptide flanked by sequences not found in association with the amino acid sequence of the peptide in nature. Another example of a heterologous peptide sequence is a construct where the peptide sequence itself is not found in nature (e.g., synthetic sequences having amino acids different as coded from the native gene). Similarly, a cell transformed with a vector that expresses an amino acid construct which is not normally present in the cell would be considered heterologous for purposes of this invention. Allelic variation or naturally occurring mutational events do not give rise to heterologous peptides, as used herein.”
Based on this cited paragraph for support, there is no support for the full amendment to claim 86, in particular wherein the adjuvant or the antigen is a nucleic acid, that are not normally associated with said anucleate cell-derived vesicle in nature. There is only mention that the amino acids of the antigen are not normally associated with said anucleate cell-derived vesicle in nature.
Secondly, in reference to the full limitation of “wherein said anucleate cell-derived vesicle has reduced ATP production and increased surface phosphatidylserine levels compared to an anucleate cell that does not comprise an antigen, an adjuvant, or both an antigen and an adjuvant,” there is no support for this comparison in the disclosure. The Specification describes the comparison in relation to the “input anucleate cells” (par 0037) or rather the “parent anucleate cell” (par 0040), yet there is no comparison with the anucleate cells currently recited in the claims.
For these reasons, the claim is rejected under 35 USC 112(a) for the introduction of “new matter” that is not supported by the instant disclosure.
Claims 93, 113, 123, 152, and 230 are rejected by dependency.
Enablement
Claims 86, 93, 113, 123, 152, and 230 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
anucleate cell-derived vesicles, wherein the anucleate cell is a red blood cell (RBC)
wherein the antigen is a peptide or polypeptide;
it does not reasonably provide enablement for the full scope of currently listed claim 86 wherein the vesicles are derived from any anucleate cells and the antigen comprising nucleotides.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and usethe invention commensurate in scope with these claims.
In determining whether Applicant’s claims are enabled, it must be found that one of skill in the art at the time of invention by applicant would not have had to perform “undue experimentation” to make and/or use the invention claimed. Such a determination is not a simple factual consideration, but is a conclusion reached by weighing at least eight factors as set forth in In re Wands, 858 F.2d at 737, 8 USPQ 1400, 2d at 1404. Such factors are: (1) The breadth of the claims; (2) The nature of the invention; (3) The state of the art; (4) The level of one of ordinary skill in the art; (5) The level of predictability in the art; (6) The amount of direction and guidance provided by Applicant; (7) The existence of working examples; and (8) The quantity of experimentation needed to make and/or use the invention.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
Claim 86 is directed to an anucleate cell-derived vesicle comprising: an antigen, an adjuvant, or both an antigen and an adjuvant; and wherein said anucleate cell-derived vesicle has reduced ATP production and increased surface phosphatidylserine (PS) levels compared to an anucleate cell that does not comprise an antigen, an adjuvant, or both an antigen and adjuvant, wherein the antigen is a nucleic acid, peptide or polypeptide and said antigen and adjuvant are not normally associated with said anucleate cell-derived vesicle in nature.
Claim 93 is directed to particular antigens and adjuvants. Claim 113 recites wherein the anucleate cell comprises a red blood cell, a platelet, or both. Claim 123 recites select properties of the anucleate cell vesicle. Claim 152 recites the anucleate cell vesicles with a pharmaceutically acceptable excipient. Claim 230 is directed to wherein the exogenous antigen, the adjuvant, or both the exogenous antigen and the adjuvant are encapsulated within the anucleate cell-derived vesicle.
(1) Quantity of experimentation needed: There is considerable experimentation required to determine the outcomes related to the production of the vesicles from different anucleate cells, e.g. reticulocytes and thrombocytes, especially in view of reduced ATP production and increased PS levels on the exterior surface of said vesicle. These characteristics are dependent on the cellular metabolism and lipid composition of the parent cell, in addition to the method of derivation of the vesicles. There is no information provided in the Specification to suggest that the same outcomes observed with RBC are expected for other anucleate cells. The Specification provides 26 examples to determine different combinations and concentrations of antigens and/or adjuvant types in addition to different order of steps to produce RBC vesicles, and therefore it is clear considerable experimentation would be required to show similar outcomes with other anucleate cell types.
Moreover, the present examples only include antigens comprising peptides and polypeptides, despite the claims being directed to antigens comprising nucleic acids. Such examples are necessary because the chemical composition between nucleic acids and amino acids are different, and therefore extensive experimentation is required to determine if the disclosed vectors are capable of comprising such antigens.
(2) Amount or direction or guidance presented & (3) the presence or absence of working examples: The entirety of the 26 examples provided in the Specification are directed to RBC derived vesicles, with no teachings of other anucleate cell-derived vesicles. Paragraph 141 states, “As used herein, "anucleate cell" refers to a cell lacking a nucleus. Such cells can include, but are not limited to, platelets, red blood cells (RBCs) such as erythrocytes and reticulocytes. Reticulocytes are immature (e.g., not yet biconcave) red blood cells, typically comprising about 1 % of the red blood cells in the human body. Reticulocytes are also anucleate.”. These cell types are further recited in paragraphs 207, 217, 218, 221, 296, 297, and 327. In relation to the antigen comprising a nucleic acid, paragraphs 17, 22, 34, 53, 62, 79, 87, 94, and 352. There are no working examples wherein the antigen comprises a nucleic acid.
(4) Nature of the invention & (8) the breadth of the claims: The claims are directed to a composition, particularly anucleate cell derived vesicles. The anucleate cell should be considered as it impacts the composition of the vesicles. For example, there is an expectation that the cellular composition across anucleate cells vary, and therefore the vesicles derived thereof would share this characteristic. The vesicles would potentially have major differences in lipid compositions, cell machinery and products thereof, and potential differences in size restrictions based on the starting cell sizes. The current claims are broad in encompassing all anucleate cells and vesicles derived thereof, despite it not being clear that the full scope can meet the limitations pertaining to ATP production and PS levels, and furthermore contain antigens and/or adjuvants.
(5) State of the prior art: The prior art teaches anucleate cell derived vesicles, particularly that of RBC (Huang et al. (US-8329161-B2; citations from US Pub. 2009/0274630-A1; of record), and platelets (Tao et al. (International journal of biological sciences 13.7 (2017): 828). Furthermore, Beleznay et al.( Biochemistry 32.12 (1993): 3146-3152; of record) teaches that RBC derived vesicles have lower ATP production in comparison to RBC, and furthermore, their lipid compositions as being similar, which is different than the instant claims that recite a higher PS level. A recent study conducted by Noulsri et al. (Laboratory Medicine 50.1 (2019): 47-53) determined determine both the quantity and intensity of PS expression of RBCs, fragmented RBCs, and RBC-derived microparticles (RMPs) [reading on vesicles] in patients with β-thalassemia/hemoglobin (Hb)E. The observed outcomes were a higher number of PS-exposing RBCs, yet a significantly higher PS expression was seen in RMPs. In relation to platelet derived vesicles, Wei et al. (Scientific Reports 8.1 (2018): 9987) describes the release of PS exposing EVs from activated platelets, further describing that “EVs shed from the plasma membrane often expose phosphatidylserine (PS) on their outer leaflet. In non-activated platelets, PS is asymmetrically restricted to the inner leaflet.” (p 1, par 2). Therefore, vesicles derived from activated platelets may have higher PS expression on the exterior in comparison to non-activated platelets which retain PS on the inner leaflet. In reference to ATP levels of platelet derived vesicles in comparison to the platelets, this is not clear based on the lack of teachings in the prior art. In reference to reticulocytes and reticulocyte-derived vesicle, there are no clear teachings in the prior art regarding the respective ATP levels and surface PS expression.
In further view of the vesicles comprising an antigen, more specifically a nucleic acid, there are teachings in the art of using vesicles for delivery of nucleic acids as supported by Usman et al. (Nature communications 9.1 (2018): 2359), wherein RBC-derived EVs are used for the delivery of RNA drugs, including antisense oligonucleotides, Cas9 mRNA, and guide RNAs (abstract). However, the instant claims are directed to a more specific anucleate derived vesicle, wherein the contents have a lower ATP level and an increased surface PS level compared to anucleate cells. Therefore, it remains unclear if the nucleic acids being comprised are capable of being encapsulated by these vesicles, and moreover remain biologically functional thereafter.
(6) Relative skill of those in the art: The level of skill in the art is high.
(7) Predictability or unpredictability of the art: There remains a high unpredictability due to the majority of research that it would require to test different anucleate cell derived vesicles, and furthermore with different antigens comprising nucleic acids. The Specification lists over 20 examples that tested only a species of the vesicles claimed in claim 86. The prior art has more teachings in relation to red blood cell derived vesicle as opposed to other anucleate cells and their derived vesicle, and therefore there remains an unpredictability with whole genus of vesicles claimed. Moreover, there is an unpredictability with vesicles comprising antigens that are nucleic acids since the working examples were only directed to amino acids (peptides and polypeptides).
In conclusion, the instant disclosure has a scope of enablement for only red blood cell derived vesicles as opposed to any anucleate cell derived vesicle, and furthermore wherein the antigen comprises a peptide or polypeptide, as opposed to a nucleic acid.
Conclusion
Claims 86, 93, 113, 123, 152, and 230 are rejected. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL A RIGA whose telephone number is (571)270-0984. The examiner can normally be reached Monday-Friday (8AM-6PM).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria G Leavitt can be reached at (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MICHAEL ANGELO RIGA/Examiner, Art Unit 1634
/TERESA E KNIGHT/Primary Examiner, Art Unit 1634