DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on January 28, 2026 has been entered.
Any prior rejection that is not repeated or addressed below is either moot or withdrawn in view of Applicant’s amendment.
Claims Summary
Claims 1, 2, 6, 27, 28, 32, 35 and 40
Claim 1 is directed to a plurality of modified PBMCs comprising an exogenous antigen intracellularly, formed by passing a cell suspension of isolated input PMBCs comprising T cells, B cells, NK cells and monocytes through a cell-deforming constriction having a width of about 3.5 microns to deliver the antigen into each of the T cells, B cells, NK cells and monocytes. The plurality of modified PBMCs exhibit improved delivery of the antigen into each of the T cells, B cells, NK cells and monocytes as compared to corresponding modified PBMCs passed through a cell-deforming constriction having a width from about 4.0 microns, or about 4.5 microns. The percentage of cells delivered with the antigen ranges between 60% and 90%. Claim 40 is directed to a composition thereof. The antigen comprises a cancer antigen, an infectious disease antigen, or a viral-disease associated antigen (claim 2). The plurality of modified PBMCs further comprises an adjuvant (claim 6). The antigen and/or adjuvant is present in at least about 70% of the cells in the plurality of PBMCs (claim 27). The adjuvant is, for example, CpG ODN, among others (claim 28). Further improved properties comprise increased expression of one or more costimulatory molecules (e.g., CD80 and/or CD86 (claim 32 and 35)), and/or increased expression of one or more cytokines (e.g., IFN-α (claims 32 and 35)).
Claims 48, 61, 62 and 96
Claim 48 is directed to a method for stimulating an immune response in an individual in need thereof, comprising:
Passing a plurality of PBMCs through a cell deforming constriction having a width of 3.5 microns, thereby causing perturbations of the PBMCs such that an antigen in contact therewith enters the PBMCs;
Incubating the plurality of PBMCs comprising the antigen with a conditioning agent for about 4, 4.5 hours, etc. or 24 hours, thus generating a conditioned plurality of PBMCs comprising the antigen;
Administering the conditioned plurality of PBMCs comprising the antigen to the individual; administration is prior to, concurrently with, or following administration of a cytokine, an immune checkpoint inhibitor, a therapeutic agent, or a combination thereof (claim 61); the cytokine is IL-15, the immune checkpoint inhibitor is targeted to PD-1, for example, and the therapeutic agent is a chemotherapeutic agent (claim 62).
The conditioned PBMCs exhibit one or more improved properties compared to a corresponding non-conditioned PBMCs passed through a cell-deforming constriction having a width of about 4.0 microns, or about 4.5 microns. The improved properties comprise improved delivery of the antigen per cell of the input PBMCs, improved antigen presentation, improved antigen-specific response, or any combination thereof. The conditioning agent comprises a CpG ODN, for example (claim 96).
Claims 67, 69, 71, 76 and 97
Claim 67 is directed to a method of producing a plurality of PBMCs, comprising passing an isolated plurality of PBMCs comprising T cells, B cells, NK cells and monocytes through a cell deforming constriction having a width of about 3.5 microns, thereby causing perturbations of the PBMCs such that an antigen enters each of the T cells, B cells, NK cells and monocytes. The conditioned plurality of PBMCs exhibit improved delivery of the antigen into each of the T cells, B cells, NK cells and monocytes compared to a corresponding plurality of PBMCs passed through a cell-deforming constriction having a width of about 4.0 microns, or about 4.5 microns. The percentage of cells delivered with the antigen ranges between 60% and 90%. The method further comprises incubating a plurality of PBMCs with a conditioning agent for about 4 to about 24 hours (claim 97). The plurality of PBMCs are passed through the cell-deforming constriction before being conditioned (claim 69). The conditioning agent comprises a CpG ODN, for example (claim 71). In another embodiment, the plurality of PMBCs is incubated with an agent that enhances the viability and/or function of the PBMCs as compared to corresponding PBMCs that have not been incubated with the agent (claim 76).
Claim Objections
Claims 1, 2, 6, 27, 28, 32, 25 and 40 are objected to because of the following informalities: Claim 1, line 4 recites “constriction-having”. The dash should be removed. Dependent claims are included in this objection. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2, 6, 27, 28, 32, 35, 48, 61, 62, 67, 69, 71, 76, 96 and 97 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
The claims recite, “improved delivery” (claims 1 and 67, for example), “one or more improved properties” (claims 32 and 48, for example), “improved antigen-presentation”, “improved antigen-specific response”, and combinations thereof. This language does not appear to be disclosed in the claims or specification as originally filed.
In the remarks filed January 28, 2026, Applicant addressed one aspect of this rejection (i.e., constriction width) which was resolved by Applicant’s amendment concerning constriction width. However, the response did not appear to address the ongoing issue of the use of the language “improved delivery”, “improved properties”, “improved antigen-presentation” or “improved antigen-specific response”. Example 12 shows increased dextran delivery. Example 13 shows an increased in IFN-gamma production. While embodiments of increased delivery and increased expression of one or more cytokines are supported by the specification, the other embodiments of “improved delivery”, etc., are not. Therefore, the rejection is maintained.
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.
(New Rejection) Claim 32 is 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.
Claim 32 recites the limitation "wherein the one or more improved properties further comprise" in claim 1. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 2, 6, 27, 28, 32, 35, 40, 67, 76 and 96 are rejected under 35 U.S.C. 102(a)(1) as anticipated by Sharei et al. (WO 2016/070136 A1, “Sharei”). The claims are summarized above and correlated with the teachings of the prior art in bold font below.
Sharei discloses immune cells and compositions thereof comprising compounds of interest, generated by passing a cell suspension of immune cells through a microfluidic device that constricts the diameter of the cells, resulting in disrupting the membrane and allowing for exogenous compounds of interest to enter the cytosol (intracellular) (see page 13, and page 5, first full paragraph, first sentence) (claims 1 and 40). PBMCs, such as T cells, B cells, NK cells, monocytes, and mixed cell populations, among others, are contemplated (see page 14, last paragraph) (claims 1 and 67). Sharei discloses isolating cells (see page 38, last two paragraphs, and page 24, first full paragraph, for example) (claims 1 and 67, aspect of isolated cells). Further, Sharei’s cells would reasonably be considered isolated at least in the sense that they are not part of a subject’s body. Constriction widths are between about 2-10 µm, such as about 3, 3.5, 4 or 3-4 µm (see page 2, second full paragraph) (claims 1 and 67). The compound(s) of interest is, for example, an antigen associated with an infectious disease, which leads to cytokine production and improved antigen-specific responses, for example (claims 1, 2, 32 and 67) (see pages 4-5, bridging paragraph, the Table on page 37, page 17, last paragraph).
Additionally, the immune cells are suitable for inducing immune responses, wherein the method of constriction exposes the immune cells to mixtures of proteins and adjuvant, thus conditioning the cells (see page 25) (claim 6). Multiple adjuvants are contemplated, including CpG ODN, and R848 which leads to IL-12 production (see page 27, fourth full paragraph, and last full paragraph) (claims 28, 32, 35 and 96). Suppressors of PD-1, PDL-1, CTLA-4 are also contemplated to for intracellular delivery to enhance cell survival and activity (see pages 27-28, bridging paragraph) (claim 76). Cells are contacted with an adjuvant after constriction, for periods of time between 5 minutes to about 2 hours, improving immune responses to the antigen (see page 26, top paragraph) (claims 1 and 67).
With regard to the newly introduced limitation in claims 1 and 67, “each of the T cells, B cells, NK cells, and monocytes” in the context of delivery of antigen, Sharei does not disclose this embodiment in these exact terms, i.e., “each of”. However, Sharei discloses the delivery of molecules via cell squeezing into a variety of target cells including T cells, B cells, monocytes/macrophages, dendritic cells, for example (see page 11-12, bridging paragraph). The implication of Sharei’s disclosure is that each type of cell, i.e., each cell, is squeezed and antigen is delivered. Sharei does not have to use the exact words “each of” in order to convey the idea that each cell is being modified.
With regard to claims 1, 27 and 67, wherein the percentage of cells delivered with the antigen ranges between 60% and 90%, and wherein the antigen and/or adjuvant is present in at least about 70% of the cells in the plurality of PBMCs, these are expected outcomes of doing what Sharei teaches, given that the same cell constriction method is utilized with the same cells and compounds.
Although Sharei does not make a comparison between constriction of a width of 3.5 microns versus about 4.0 and about 4.5 microns, regarding the outcomes of improved delivery, or other improvements, such a comparison is not necessary for Sharei to anticipate the claimed invention. Since Sharei discloses constriction at a width of 3.5 microns, any immune outcomes are inherent to using that width for constriction (claims 1, 32 and 67, aspect of a comparison between constriction at a width of 3.5 microns and about 4.0/about 4.5 microns). Therefore, the claims are anticipated by the prior art.
Applicant’s arguments filed January 28, 2026 have been carefully considered but fail to persuade. Applicant’s arguments are directed to the following:
Applicant argues that the claims recite the limitation of a constriction width of about 3.5 microns. Applicant asserts that Sharei’s disclosure regarding the constriction width is a range of 2-10 microns. Applicant argues that the larger range of 2-10 microns does not anticipate the narrower range of about 3.5 microns. Applicant also argues that Sharei did not appreciate that the criticality of the value of about 3.5 microns that provides improved properties compared to the values of about 4.0 and about 4.5 microns, such as improved antigen delivery.
In response, Sharei discloses constriction widths as a range of about 2-10 µm, as well as narrower values such as about 3.5 µm (see page 2, second full paragraph). Since Sharei discloses a constriction value of about 3.5 µm, Applicant’s argument is not persuasive. By following Sharei’s suggestion to use a constriction width of about 3.5 µm, one would have achieved the improved properties observed by Applicant regardless of whether a comparison was made with other constriction values.
Applicant argues that Sharei does not disclose isolated PBMCs.
In response, Sharei discloses isolating cells (see page 38, last two paragraphs, and page 24, first full paragraph, for example). Further, Sharei’s cells would reasonably be considered isolated at least in the sense that they are not part of a subject’s body.
Applicant argues that Sharei does not teach delivery of antigen into each subset of a plurality of cells.
Sharei discloses the delivery of molecules via cell squeezing into a variety of target cells including T cells, B cells, monocytes/macrophages, dendritic cells, for example (see page 11-12, bridging paragraph). The implication of Sharei’s disclosure is that each type of cell, i.e., each cell, is squeezed and antigen is delivered. Sharei does not have to use the exact words “each of” in order to convey the idea that each cell is being modified.
Applicant argues that Sharei does not teach a specified percentage range of cells that are modified.
This is an expected outcome of doing what Sharei teaches, given that the same cell constriction method is utilized with the same cells and compounds.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 2, 6, 27, 28, 32, 35, 40, 48, 61, 62, 67, 69, 71, 76, 96 and 97 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-36 and 38 of U.S. Patent 11,692,168 B2 in view of Sharei et al. (WO 2016/070136 A1, “Sharei”). Although the claims at issue are not identical, they are not patentably distinct from each other. The instant claims specify that the PBMCs are mixed population of T cells, B cells, NK cells and monocytes, and that the effect of the constriction of the cells is a variety of improved properties recited in the claims. The patented claims do not specify the composition of the PBMCs, nor the improved properties associated with a 3.5 micron width constriction. However, it would have been obvious to have claimed a more specific embodiment, such as a mixed population with a reasonable expectation of success in view of Sharei’s teachings regarding constriction of a mixed population of PBMCs for the same purpose of introducing antigen into the cells (see page 13, and page 5, first full paragraph, first sentence, and page 14, last paragraph), as well as the constriction width of about 3.5 µm (see page 2, second full paragraph). As for the improved properties and percentages of modified cells, these are natural outcomes of the patented methods/products.
Claims 1, 2, 6, 27, 28, 32, 35, 40, 48, 61, 62, 67, 69, 71, 76, 96 and 97 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-145 of U.S. Patent 11,111,472 B2 in view of Sharei et al. (WO 2016/070136 A1, “Sharei”). Although the claims at issue are not identical, they are not patentably distinct from each other.
The patented claims are directed to methods of engineering immune cells, such as T cells, B cells, dendritic cells, NK cells, monocytes, and mixed populations, to comprise a compound, such as HPV antigen. The copending claims do not recite the improved properties regarding the width of constriction being 3.5 microns instead of about 4.0 microns or about 4.5 microns. However, Sharei discloses a constriction width of about 3.5 µm (see page 2, second full paragraph). It would have been obvious to have incorporated Sharei’s teachings into the copending claims since they are directed to similar methods disclosed by Sharei (i.e., cell squeezing for antigen presentation). As for the improved properties and percentages of modified cells, these are natural outcomes of the patented methods/products.
With regard to instant claim 27, wherein the antigen and/or adjuvant is present in at least about 70% of the cells in the plurality of PBMCs, this is an expected outcome of the patented methods, given that the same cell constriction method is utilized with the same cells and compounds.
Instant claims 28 and 96 are directed to particular adjuvants, whereas patented claims 1, 17, 70 and 113 only recite a generic adjuvant. It would have been obvious to have claimed particular adjuvants, such as those listed in claims 28 and 96, with a reasonable expectation of success, in view of Sharei et al., which discloses a similar method and modified PBMCs, wherein adjuvants are contemplated, including CpG ODN and R848 (see page 27, last full paragraph).
Claims 1, 2, 6, 27, 28, 32, 35, 40, 48, 61, 62, 67, 69, 71, 76, 96 and 97 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 145 of US Patent 12,410,392 B2 (issued from Application No. 17/394,125) in view of Sharei et al. (WO 2016/070136 A1, “Sharei”). Although the claims at issue are not identical, they are not patentably distinct from each other. The instant claims specify that the PBMCs are mixed population of T cells, B cells, NK cells and monocytes, and that the effect of the constriction of the cells is a variety of improved properties recited in the claims. The patented claim is directed to T cells and does not recite the improved properties regarding the width of constriction being 3.5 microns instead of about 4.0 microns or about 4.5 microns. However, the copending claim is not limited to T cells because the claim language is open (i.e., comprising). It would have been obvious to have claimed a mixed population with a reasonable expectation of success in view of Sharei’s teachings regarding constriction of a mixed population of PBMCs for the same purpose of introducing antigen into the cells (see page 13, and page 5, first full paragraph, first sentence, and page 14, last paragraph), as well as the constriction width of about 3.5 µm (see page 2, second full paragraph). As for the improved properties and percentages of modified cells, these are natural outcomes of the patented method. All other limitations of the instant claims would have been obvious to claim in view of Sharei’s teachings.
Claims 1, 2, 6, 27, 28, 32, 35, 40, 48, 61, 62, 67, 69, 71, 76, 96 and 97 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 186, 188, 213, 215, 272 and 311-314 of copending Application No. 16/980,341 (reference application) in view of Sharei et al. (WO 2016/070136 A1, “Sharei”).
The copending claims are directed to methods of treating an HPV-associated disease by administering a composition comprising modified immune cells to a patient, wherein the modified immune cells comprise an HPV antigen and an adjuvant, with limitations throughout the claims that read on the same embodiments of types of cells and adjuvants. Also claimed are modified cells and conditioned, modified PBMCs, as well as mixed cell populations.
The copending claims do not recite the improved properties regarding the width of constriction being 3.5 microns instead of about 4.0 microns or about 4.5 microns. However, Sharei discloses a constriction widths of about 3.5 µm (see page 2, second full paragraph). It would have been obvious to have incorporated Sharei’s teachings into the copending claims since they are directed to similar methods disclosed by Sharei (i.e., cell squeezing for antigen presentation). As for the improved properties and percentages of modified cells, these are natural outcomes of the patented methods/products. With regard to instant claim 27, wherein the antigen and/or adjuvant is present in at least about 70% of the cells in the plurality of PBMCs, this is an expected outcome of the copending claims’ methods, given that the same cell constriction method is utilized with the same cells and compounds.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 2, 6, 27, 28, 32, 35, 40, 48, 61, 62, 67, 69, 71, 76, 96 and 97 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 82, 83, 88, 92, 96, 98, 99, 104, 106, 121, 133, 154, 156, 178, 180, 194, 197, 213, 289 and 290 of copending Application No. 18/043,613 (reference application) in view of Sharei et al. (WO 2016/070136 A1, “Sharei”).
Although the claims at issue are not identical, they are not patentably distinct from each other. The copending claims are directed to a composition of nucleated cells, such as PBMCs, including T cells, B cells, NK cells, combinations thereof, etc., conditioned with an adjuvant (claim 121), comprising an antigen such as HPV. Also claimed are methods for producing the cells and methods of inducing an immune response with the modified cells. The copending methods render obvious the products used in the methods. The copending claims do not recite the improved properties regarding the width of constriction being 3.5 microns instead of about 4.0 microns or about 4.5 microns. However, Sharei discloses a constriction widths of about 3.5 µm (see page 2, second full paragraph). It would have been obvious to have incorporated Sharei’s teachings into the copending claims since they are directed to similar methods disclosed by Sharei (i.e., cell squeezing for antigen presentation). As for the improved properties and percentages of modified cells, these are natural outcomes of the patented methods/products. With regard to instant claim 27, wherein the antigen and/or adjuvant is present in at least about 70% of the cells in the plurality of PBMCs, this is an expected outcome of the copending claims’ methods, given that the same cell constriction method is utilized with the same cells and compounds.
Instant claims 28 and 96 are directed to particular adjuvants, whereas copending claim 136 only recites a generic adjuvant. It would have been obvious to have claimed particular adjuvants, such as those listed in claims 28 and 96, with a reasonable expectation of success, in view of Sharei et al., which discloses a similar method and modified PBMCs, wherein adjuvants are contemplated, including CpG ODN and R848 (see page 27, last full paragraph). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
In the remarks filed January 28, 2026, Applicant requests that all of the obviousness type double patenting rejection be held in abeyance until allowable subject matter is identified.
Conclusion
No claim is allowed.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to Stacy B. Chen whose telephone number is 571-272-0896. The examiner can normally be reached on M-F (7:00-4:30). If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas Visone, can be reached on 571-270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
/STACY B CHEN/Primary Examiner, Art Unit 1672