DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Applicant’s claim to priority from US Provisional Application No. 63/306,140 filed 02/03/2022 is hereby acknowledged.
Election/Restrictions
Newly submitted claims 26-28 directed to an invention that is independent or distinct from the invention originally claimed for the following reasons:
Claims 1-4, 8, 11-14, 17-19 and newly added claims 23-25 are drawn to an mRNA immunotherapeutic vaccine (Invention Group I), while claims 26-28 are drawn to a method for manufacturing an immunotherapeutic vaccine (Invention Group II). The method of manufacturing is a newly claimed invention.
The inventions are independent or distinct, each from the other because:
Inventions Group I and Group II are related as process of making and product made. The inventions are distinct if either or both of the following can be shown: (1) that the process as claimed can be used to make another and materially different product or (2) that the product as claimed can be made by another and materially different process (MPEP § 806.05(f)). In the instant case, the immunotherapeutic mRNA vaccine can be obtained using two different immunogenic mRNA constructs, transfecting them separately in two cells of different types and transferring both cells via adoptive cell transfer using a single infusion.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits.
Accordingly, claims 26-28 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Application Status
Amendments to claim filed 01/22/2026 are hereby acknowledged. Claims 1-4, 8, 11-14, and 17-19 are currently amended. Claims 5-7, 9-10, 15-16 and 20-22 are cancelled. Claims 23-28 are newly added. Therefore, claims 1-4, 8, 11-14, 17-19 and 23-28 are pending. Claims 26-28 are withdrawn from consideration as being directed to non-elected invention Group II. Thus, claims 1-4, 8, 11-14, 17-19 and 23-25 are under consideration in this Office Action.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 02/17/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The disclosure was previously objected to because it contained an embedded hyperlink and/or other form of browser-executable code (pages 19-20). Applicant was required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code, according to MPEP § 608.01.
Instead Applicant deleted pages 19 and 20, without proving a substitute copy of the Specification.
Response to Amendment
Applicant requested deletion of pages 19 and 20 of the Specification on 01/22/2026 as a response to objection. Therefore the objection to Specification is withdrawn.
However, Applicant did not provide with “strikethrough/ marked” copy and/or clean copy of Specification. Therefore, the amendment is not compliant under MPEP §714 (II) (B).
NOTE: Applicant should also file the list of references in a new IDS.
Claim Objections
Claim 17 is objected to because of the following informalities: the claim recites “wherein the non-secretable complex additional comprises a TMD fragment”. The claim should read “ wherein the non-secretable complex additionally comprises a TMD fragment”. Appropriate correction is required.
The following rejections are new as necessitated by Applicant’s amendments:
Claim Rejections - 35 USC § 112(b)
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 19, 23-25 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 19, it recites the limitation "wherein said TMD fragment is from
the transmembrane domain of the target-antigen or from the CD40L ligand" .
There is insufficient antecedent basis for this limitation in the claim. Claim 19 depends on claim 17, which does not recite a CD40L ligand.
Regarding claims 23-25, they recite the terms “each complex adapted to build protein”. There is no definition for “complex adapted to build protein” in the disclosure. Therefore, in absence of a clear definition in the Specification, Examiner consulted definitions in Biology. A “complex adapted to build protein” primarily refers to a ribosome.
Claims 24 and 25 are dependent claims that do not remedy the deficiencies of claims 23. Therefore, these claims are rejected as well.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 1-4, and 8 are rejected under 35 U.S.C. § 103 as being unpatentable over Xiang (Xiang, R. et al. "A dual-function DNA vaccine encoding Carcinoembryonic Antigen and CD40 Ligand trimer induces T cell-mediated protective immunity against colon cancer in Carcinoembryonic Antigen-transgenic mice". The Journal of Immunology, Vol. 167 (2001), pp: 4560-4565; cited on IDS filed 02/17/2026), in view of Fanslow (Fanslow, W.C. et al. " Structural characteristics of CD40 ligand that determine biological function". Seminars in Immunology, Vol. 6 (1994), pp: 267-278), Gupta (Gupta, S. et al. "A multi-trimeric fusion of CD40L and gp100 tumor antigen activates dendritic cells and enhances survival in a B16-F10 melanoma DNA vaccine model". Vaccine, Vol. 33 (2015), pp: 4798-4806) and McNamara (McNamara, M.A. et al. “RNA-based vaccines in Cancer Immunotherapy”. Journal of Immunology Research, Vol. 2015 (2015), ID: 794528; previously cited).
Regarding claim 1, it recites :
“An immunotherapeutic mRNA vaccine, for administration to an individual in a single administration of a vaccine adapted to generate a cellular and humoral immune response against a disease by therapeutic stimulation through two or more immunostimulatory interacting pathways, comprising an encoding region having at least two translation units, comprising:
a first translation unit comprising a nucleic acid encoding for a secretable first fusion protein comprising a first costimulatory molecule fused to a first target-antigen, adapted to generate a first target-antigen immune response by way of a MHC Class II binding immunostimulatory pathway, and
a second translation unit comprising a nucleic acid encoding for a non-secretable second fusion protein comprising an identical second co-stimulatory molecule to the first co-stimulatory molecule fused to a second target-antigen identical to the first target-antigen, adapted to generate a second target-antigen immune response by way of a MHC Class I binding immunostimulatory pathway.”
Regarding claim 1, Xiang teaches a single DNA vaccine with dual function, encoding a Carcinoembryonic Antigen (CEA) and CD40 Ligand trimer which induces T cell-mediated immune response against colon cancer (see title and abstract). Xiang teaches that CEA is an oncofetal membrane antigen, that is a tumor self-antigen target (see page 4560, left column).
Xiang teaches a construct that can be a plasmid encoding the CD40LT gene comprising a modified 33-aa leucine zipper motif to facilitate the formation of trimeric CD40L that was fused to the C-terminus of the IL-7 leader sequence to direct protein expression to the cell surface or induce its secretion outside the cells. Xiang teaches that the plasmid construct pCD40LT-CEA contains the entire CEA extracellular domain fused to the C-terminus of murine CD40L, thus generating a dual-function chimeric construct (see page 4561, right column, “Construction of expression plasmids” section).
Xiang teaches that the single construct vaccine is capable of increasing MHC Class I antigen-restricted cytotoxicity of CTLs (see abstract). Xiang teaches that the vaccine is capable of activating both dendritic cells and naïve T lymphocytes and provides evidence that vaccination with pCD40LT-CEA molecules induces and enhances the expression of costimulatory molecules on CD11c+ and MHC Class II antigen-positive DCs (see page 4563, right column, second paragraph).
Xiang also teaches that a membrane-bound cell surface expressed fusion CD40L-CEA molecule encoding construct leads to increase of secretion of proinflammatory cytokines IFN-ɣ and IL-12 (see abstract, and page 4564, left column, “pCD40LT-CEA vaccination enhances production of cytokines boosted further by Ab-IL-2 fusion protein” section).
Xiang does not teach a first and a second translation units. Xiang refers to reference # 16 for the dual-function construct, which is Fanslow.
Fanslow teaches different constructs encoding soluble CD40L, with comparable biological potency to that of the membrane-associated CD40L (see page 268, right column). Fanslow teaches that membrane CD40L are capable of activating B cells, at the same level of a soluble trimeric CD40L. Fanslow teaches that upon costimulation, a soluble trimeric CD40L can activate B cells’ proliferation and differentiation at the same level of a membrane CD40L (see Table 1, see below).
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Therefore, Fanslow teaches that costimulation always maximizes B cell responses (see above).
Fanslow also teaches that “It appears, therefore, that a higher degree of CD40 crosslinking or a more sustained signal may be required to induce T cell proliferation, compared to that sufficient to drive B cells into cell cycle” (see page 273, left column, first paragraph). Fanslow further teaches that “Binding of immobilized ligand and antibody may well provide for a greater degree of crosslinking and lead to a prolonged period of signaling compared to that delivered by soluble CD40L or CD40 Mab which could be rapidly internalized or shed from the cell surface” (see page 275, left column, third paragraph).
Gupta teaches that a multi-trimeric fusion of CD40L and gp100 tumor antigen activates dendritic cells and enhances survival in a melanoma-bearing subjects (see title and abstract).
Gupta teaches that “one approach to increase DNA vaccine efficacy is to encode molecular adjuvants within the vaccine”, said molecular adjuvants include cytokines/chemokines as well as members of the TNF superfamily ligands such as CD40L, involved in DC activation (see page 4798, right column). However, Gupta also teaches that cytokines as DNA-encoded adjuvants for DNA vaccines showed modest efficacy (see “Introduction” section, page 4799, left column, lines 18-23).
Gupta teaches that a fusion protein encoded by the murine CD40L extracellular domain fused to the collagen-like domain of murine SPD, with gp100 antigen inserted within the SPD coding region, is a soluble (i.e., secretable) CD40L trimer that delivers gp100 to DC while simultaneously activating the DC, thereby inducing an enhanced anti-tumor CD8+ T cell response (see “Introduction” section, page 4799, left column, lines 24-30).
Gupta also teaches that the soluble CD40L protein encoding construct did not inhibit tumor growth alone (see page 4801, left column, section 3.4). However, Gupta also teaches that the construct is significantly more efficient when combined with plasmids encoding other adjuvants such as pGM-CSF and pIL-12p70 (see section 3.5., page 4801).
Therefore, as it is suggested by Fanslow in Table 1 and the teachings of Gupta, it is obvious that a construct encoding a membrane CD40L molecule supplemented with a construct encoding a soluble CD40L molecule would maximize the activation, proliferation and differentiation of B cells after vaccination.
It would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have combined the membrane-associated fusion protein [CD40LT-tumor target antigen] encoding construct as taught by Xiang, with a soluble fusion protein [trimeric CD40L-tumor target antigen] encoding construct as taught by Gupta and modified according to Fanslow and Xiang, within a single vaccine. One with ordinary skills motivated in maximizing the immune response, obtaining activation of both MHC Class I and Class II pathways, and obtaining increases in secretion of cytokines, therefore prolonging the period of signaling and immune response could have modified the constructs and gotten a combination within a single vaccine that induces these immune responses. One with ordinary skills in the art could have performed this modification with a reasonable expectation of success and arrived at the claimed invention.
The combination of Xiang, Fanslow and Gupta does not teach RNA-based vaccines.
However, McNamara teaches RNA-based vaccines used in cancer immunotherapy (see title). McNamara teaches that RNA vaccines consist of messenger RNA synthesized by in vitro transcription using a bacteriophage RNA polymerase and template DNA that encodes the antigens of interest (see Abstract).
McNamara teaches that DNA vaccines elicit less of an immune response than other types of vaccines, especially RNA vaccines. The relatively poor immunogenicity of DNA vaccines combined with concerns about their potential for oncogenesis via integration into the host genome has driven a shift away from DNA vaccines and towards RNA vaccines (see page 2, left column, third and fourth paragraphs).
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have transcribed in vitro the DNA sequences of interest into mRNA and integrated them into vectors to obtain mRNA vaccines as taught by McNamara (see abstract). It would have been obvious to have substituted the DNA vaccines taught by Xiang modified with Fanslow/Gupta, for mRNA vaccines as taught by McNamara. One with ordinary skills in the art, motivated in a safe construct, could have performed this modification with a reasonable expectation of success since converting DNA into mRNA by in vitro transcription is routine in the art, and arrived at the claimed invention.
Regarding claim 2, Xiang teaches a non-secretable (i.e., non-soluble) fusion protein, a protein that comprises CD40L and can be expressed on cell surface (page 4561, right column, “Construction of expression plasmids” section).
Fanslow teaches membrane-associated CD40L can induce B cell proliferation (see Table 1, and page 270, left column, lines 10-15).
Examiner interprets that for cell surface expression, CD40L is using its transmembrane domain.
The obviousness of the combination of references Xiang, Fanslow and Gupta is described above. Therefore, since Xiang and Fanslow teach cell membrane-associated CD40L, the combination of references also renders elements of claim 2 obvious.
Regarding claims 3 and 8, Xiang teaches a recombinant fusion protein combining CD40L and a target antigen encoded in a DNA construct, capable of inducing both a MHC Class I and Class II immune responses and increasing secretion of cytokines (see title and abstract).
Fanslow teaches that costimulation always maximizes B cell responses (see Table 1).
Fanslow also teaches that “It appears, therefore, that a higher degree of CD40 crosslinking or a more sustained signal may be required to induce T cell proliferation, compared to that sufficient to drive B cells into cell cycle” (see page 273, left column, first paragraph). Fanslow further teaches that “Binding of immobilized ligand and antibody may well provide for a greater degree of crosslinking and lead to a prolonged period of signaling compared to that delivered by soluble CD40L or CD40 Mab which could be rapidly internalized or shed from the cell surface” (see page 275, left column, third paragraph).
The obviousness of the combination of references Xiang, Fanslow and Gupta is described above.
It would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have combined the membrane-associated fusion protein [CD40LT-tumor target antigen] encoding construct as taught by Xiang, with a soluble fusion protein [trimeric CD40L-tumor target antigen] encoding construct as taught by Gupta and modified according to Fanslow and Xiang, within a single vaccine. One with ordinary skills motivated in maximizing the immune response, obtaining activation of both MHC Class I and Class II pathways, and obtaining increases in secretion of cytokines, therefore prolonging the period of signaling and immune response could have modified the constructs and gotten a combination that induces these immune responses as taught by Xiang. One with ordinary skills in the art could have performed this modification with a reasonable expectation of success and arrived at the claimed invention.
Therefore, since Xiang teaches activation of both signal pathways and cytokines secretion using a single construct encoding a fusion protein combining CD40L and a target antigen, the combination of references also renders elements of claim 3 obvious.
Regarding claims 4 and 17, they recite “An immunotherapeutic mRNA vaccine according to claim 3, wherein the first immune response is adapted to be induced for a first period of time by way of said MHC Class II immunostimulatory pathway and the second immune response is adapted to be induced for a second period of time by way of the MHC Class I immunostimulatory pathway, and wherein said pathways interact in an auto-stimulatory fashion and increase the amplification and prolongation of said first and second immune responses over functionally inherent amplification and prolongation”(claim 4) ; and “An immunotherapeutic mRNA vaccine for administration to a patient, comprising two separate complexes, comprising: a secretable complex adapted to induce a first immune response for migration through a first immune response pathway; and a non-secretable complex adapted to induce a second immune response for migration through a second immune response pathway; wherein each of said complexes comprises a similar co- stimulatory protein and at least one similar target-antigen, wherein the non-secretable complex additional comprises a TMD fragment, and wherein, upon administration, said pathways are adapted through crosstalk to amplify and delay in time each of said first and second immune responses, and further adapted to activate a cytokine release” (Claim 17).
Xiang’s teaching suggests the use of membrane domain of CD40L; Xiang discloses the use of CEA extracellular domain fused to the C-terminus (ecd) of CD40L and the use of a leader sequence IL-7 to direct protein expression to the cell surface (see page 4561, “Construction of expression plasmids” section).
Fanslow teaches the use of membrane-associated CD40L (see Table 1). Therefore, Examiner interprets that the naturally occurring transmembrane domain of CD40L is used to express the fusion protein at the cell surface.
Xiang teaches that vaccination with a dual-function DNA vaccine encoding a CD40L fused to a target antigen contributes to increase in secretion of proinflammatory cytokines such as IFN-ɣ (see abstract).
Fanslow teaches that CD40’s expression present on peripheral blood monocytes is enhanced following exposure to cytokines such as IFN-ɣ (see page 273, left column, second paragraph). Fanslow further teaches that in combination with cytokines, CD40L can induce monocytes to secrete IL-6, IL-8 and TNF (see page 273, left column, second paragraph). These teachings suggest an auto-stimulatory feedback pathway.
Fanslow also teaches that costimulation always maximizes B cell responses (see Table 1).
Fanslow also teaches that “It appears, therefore, that a higher degree of CD40 crosslinking or a more sustained signal may be required to induce T cell proliferation, compared to that sufficient to drive B cells into cell cycle” (see page 273, left column, first paragraph). Fanslow further teaches that “Binding of immobilized ligand and antibody may well provide for a greater degree of crosslinking and lead to a prolonged period of signaling compared to that delivered by soluble CD40L or CD40 Mab which could be rapidly internalized or shed from the cell surface” (see page 275, left column, third paragraph).
These teachings suggest crosstalks between B cells and T cells signaling.
The Specification states that “(i) a first translation unit (TU #1) which encodes a first sigTAA/ecdCD40L fusion protein which is secretable by virtue of it not having any amino-acid sequences which could be considered as transmembrane domain (TMD) sequences (which is referred to as the secretable, "prime" or extracellular pathway), and (ii) a second translation unit (TU #2) which encodes a second fusion protein (TAA/TMD/CD40L) which is non-secretable by virtue of its having amino-acid sequences considered as TMD sequences (referred to as the nonsecretable, "boost" or intracytoplasmic pathway), resulting after IM administration, in the activation of at least two or more distinct immuno-stimulatory pathways that interact in an autostimulatory fashion. The overall interaction of two or more immunostimulatory pathways which are initiated by a single vaccination, induces high and prolonged levels of innate, adaptive, humoral and cellular immune responses.”(see pages 1-2, “Summary” of the invention” section).
Therefore, Examiner interprets that a secretable recombinant CD40L fused with a target antigen protein will trigger a prime immune response, via an extracellular pathway, and a non-secretable recombinant CD40L fused with a target antigen protein will trigger a distinct, second immune pathway that is intracellular to cells expressing the membrane-bound protein. Examiner interprets that activation of their respective pathways, one extracellular and one intracellular are inherent functions of the two forms of recombinant fusion proteins.
Therefore, the amplification of B cells responses noted in Fanslow in Table 1, when there is costimulation, is interpreted as a stimulation and increase over the functionally inherent amplification and prolongation.
It would have been obvious to one with ordinary skills in the art, before the effective filing date, to have combined a construct encoding a membrane-associated CD40L fused with a target antigen as taught by Xiang modified by Fanslow and Gupta, with a construct encoding a secretable CD40L fused to a target antigen as taught by Xiang and Gupta. One with ordinary skills in the art motivated in amplifying and prolonging the immune response over the inherent amplification and prolongation of MHC Class I and Class II responses and crosstalks observed by Xiang, as taught by Fanslow (see Fanslow, Table 1) could have performed these modifications to the vaccine, combining both constructs, and obtained the amplified immune response as claimed, with a reasonable expectation of success, and arrived at the claimed invention.
Claims 11-14, 18-19 and 23-25 are rejected under 35 U.S.C. § 103 as being unpatentable over Xiang (Xiang, R. et al. "A dual-function DNA vaccine encoding Carcinoembryonic Antigen and CD40 Ligand trimer induces T cell-mediated protective immunity against colon cancer in Carcinoembryonic Antigen-transgenic mice". The Journal of Immunology, Vol. 167 (2001), pp: 4560-4565; cited on IDS filed 02/17/2026), in view of Fanslow (Fanslow, W.C. et al. " Structural characteristics of CD40 ligand that determine biological function". Seminars in Immunology, Vol. 6 (1994), pp: 267-278), Gupta (Gupta, S. et al. "A multi-trimeric fusion of CD40L and gp100 tumor antigen activates dendritic cells and enhances survival in a B16-F10 melanoma DNA vaccine model". Vaccine, Vol. 33 (2015), pp: 4798-4806) and McNamara (McNamara, M.A. et al. “RNA-based vaccines in Cancer Immunotherapy”. Journal of Immunology Research, Vol. 2015 (2015), ID: 794528; previously cited), as applied to claim 17 above and in further view of USPAT’667 (US Patent No. 10, 130, 667 B1; published November 20, 2018; previously cited).
The combination of references Xiang, Fanslow and Gupta renders obvious a combination of a membrane-associated fusion protein [CD40LT-tumor target antigen] encoding construct as taught by Xiang, with a soluble fusion protein [trimeric CD40L-tumor target antigen] encoding construct as taught by Gupta and modified according to Fanslow and Xiang, within a single vaccine. The combination of references as described above renders obvious a vaccine that can maximize the immune response, obtain activation of both MHC Class I and Class II pathways, and obtain increases in secretion of cytokines, therefore prolonging the period of signaling and immune response.
The rejection of claim 17 is described above.
The combination of references Xiang, Fanslow and Gupta also renders elements of claim 17 obvious.
However, the combination of references does not render obvious a secretable sig-TAA/ecdCD40L first fusion protein and a non secretable sig-TAA/TMD/ecdCD40L second fusion protein (claims 11-14, 18-19 and 23-25).
However, USPAT’667 teaches these elements, as described below.
Regarding claims 11, 18 and 23-25, USPAT’ 667 teaches a nucleic acid vaccine, which is transcribed into mRNA (see column 1, lines 34-41). Therefore, it teaches a DNA vaccine, identified as a “transcription unit” that is in operable linkage with a transcriptional and/or translational expression control elements (see column 6, lines 46-59). USPAT’667 teaches that the vaccine is immunotherapeutic (see column 2, lines 34-36). USPAT’667 teaches that the vaccine when administered enhances the immune response (see column 6, lines 9-14). USPAT’667 teaches that the vector can induce an adaptive humoral and cellular immune response (see column 7, lines 55-59; column 9, lines 12-13).
USPAT’667 teaches a transcription unit #1 and a transcription unit #2 (see column 9, lines 16-20). USPAT’667 teaches a construct with a first transcription unit TAA/ecdCD40L and a secondary transcription unit E1ACDA (see column 2, lines 42-53).
USPAT’667 teaches that the TAA/ecdCD40L vaccine is based on the attachment of a fragment of a target associated antigen (TAA) fused to the extracellular domain (ecd) of the potent immunostimulatory signal CD40 ligand (CD40L) (see column 2, lines 55-58). USPA’667 teaches that the vaccine can be an expression vector encoding TAA/ecdCD40L such as the adenoviral vector (Ad-sig-TAA/ecdCD40L vector) (see column 2, lines 58-63). USPAT’667 teaches that the vector (i.e. transcription/translation unit) comprises sequence coding for a secretable fusion protein comprising a co-stimulatory molecule fused to a TAA (see column 2, lines 55-63 and column 9, lines 13-20).
USPAT’667 teaches two subcutaneous injections using a TAA/ecdCD40L protein produced by a different plasmid, following initial priming injection of the Ad-sig-TAA/ecdCD40L vaccine (see column 3, lines 11-17). Therefore, USPAT’667 does teach a second fusion protein comprising an identical TAA and an identical co-stimulatory molecule.
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have substituted, within the vaccine taught by Xiang modified by Fanslow and Gupta, the secretable fusion protein encoding transcription unit taught by Xiang/Fanslow/Gupta, with a secretable transcription unit as taught by USPAT’667, i.e., secretable TAA/ecdCD40L fusion protein. It would have been obvious to use the same target antigen in both constructs to combine and obtain optimum immune responses as taught by Xiang and Fanslow.
One with ordinary skills in the art motivated in optimizing a single administration vaccine could have performed this modification with a reasonable expectation of success and arrived at the claimed invention.
Regarding claims 12 and 13, Xiang teaches that the single construct vaccine is capable of increasing MHC Class I antigen-restricted cytotoxicity of CTLs (see abstract). Xiang teaches that the vaccine is capable of activating both dendritic cells and naïve T lymphocytes and provides evidence that vaccination with pCD40LT-CEA molecules induces and enhances the expression of costimulatory molecules on CD11c+ and MHC Class II antigen-positive DCs (see page 4563, right column, second paragraph).
Xiang also teaches that vaccination with the dual-function DNA vaccine increases secretion of proinflammatory cytokines IFN-ɣ and IL-12 (see abstract). Fanslow also teaches that “It appears, therefore, that a higher degree of CD40 crosslinking or a more sustained signal may be required to induce T cell proliferation, compared to that sufficient to drive B cells into cell cycle” (see page 273, left column, first paragraph). Fanslow further teaches that “Binding of immobilized ligand and antibody may well provide for a greater degree of crosslinking and lead to a prolonged period of signaling compared to that delivered by soluble CD40L or CD40 Mab which could be rapidly internalized or shed from the cell surface” (see page 275, left column, third paragraph).These teachings suggest crosstalks between B cells and T cells signaling.
Therefore, the combination of references Xiang, Fanslow, Gupta and USPAT’667 renders elements of claims 12 and 13 obvious as well. The obviousness of the combination of references is described above.
Regarding claim 14, Xiang teaches using the dual-function vaccine in colon cancer subjects (i.e., mice; see title, abstract and page 4561, right column, “Oral immunization, tumor cell challenge, and Ab-IL-2 fusion protein boosts” section).
Gupta teaches vaccinating melanoma-bearing mice using a nucleic acid molecule encoding a secretable CD40L fused to a target antigen (see title and abstract).
USPAT’667 teaches using a nucleic acid molecule encoding a secretable CD40L fused to a target antigen protein and combination of constructs for cancer therapy (see column 1, lines 15-18).
Therefore, the combination of references Xiang, Fanslow, Gupta and USPAT’667 renders elements of claim 14 obvious. The obviousness of the combination of references is described above.
Regarding claim 19, Xiang teaches that the recombinant protein can be expressed at the cell surface (see page 4561, “Construction of expression plasmids”). Fanslow teaches the use of membrane-associated CD40L (see Table 1).
USPAT’667 teaches that the CD40L can comprise any portion of the molecule, which can be cytoplasmic domain, transmembrane region and extracellular domain (see column 6, lines 60-67).
Therefore, it would have been obvious to one with ordinary skills before the effective filing date of the claimed invention to have combined the teachings of Xiang, Fanslow, Gupta with the teachings of USPAT’667 and used a transmembrane fragment from the CD40L protein according to all three references Xiang, Fanslow and USPAT’667, when constructing the membrane-associated CD40L fused with a tumor target antigen as taught by Xiang, Fanslow and USPAT’667. One with ordinary skills in the art, motivated in providing a recombinant fusion protein with a naturally occurring transmembrane domain could have used the transmembrane fragment from CD40L with a reasonable expectation of success and would arrived at the claimed invention.
Thus, the combination of references Xiang, Fanslow, Gupta and USPAT’667 renders elements of claim 19 obvious.
Response to Arguments
Applicant’s arguments with respect to claims 1-4, 8, 11-14, 17-19 and 23-25 have been considered but are moot because the new ground of rejections do not rely on the same combination of references applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Regarding Applicant’s arguments on pages 12-13 of Remarks filed 01/22/2026, Applicant states that “USPAT’667 does not disclose or suggest an mRNA vaccine for administration to an individual in a single administration of a vaccine as recited in amended claim 1” and “Such a change would not have been obvious to one of ordinary skill in the art. That is, such a “modification” of USPAT’667 would be a material change in USPAT’667 as to its design, structure, strategy, approach and biological operation.”
In response, USPAT’667 is not the primary reference in the new grounds of rejections. Xiang is the primary reference in which a single vaccine is being administered (see title and abstract). Xiang also teaches that the recombinant fusion protein comprising a CD40L and a target tumor antigen can be modified in such a way that it is either expressed at the cell surface or secreted (see page 4561, “Construction of expression plasmids” section).
Taken in combination with Fanslow that teaches membrane-associated CD40L, and Gupta that that also teaches a fused CD40L with a target antigen, one with ordinary skills in the art could have substituted a vaccine requiring boosters with a complete vaccine comprising two constructs comprising CD40L fused to target antigen, with a reasonable expectation of success. Mc Namara teaches RNA vaccines as safer. Therefore, it would be obvious to substitute DNA constructs with RNA constructs within the vaccine. The claimed activation and prolongation, and crosstalks between immune response pathways are end-results inherent to combining two constructs having separate effects as taught by Fanslow (Table 1) once combined to be administered in a single vaccine.
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.
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/A.D./Examiner, Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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