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
The instant application claims priority to U.S. Provisional Applications 63/365,327, filed May 25, 2022, and 63/366,127, filed June 9, 2022.
Regarding claims 1, 8, and 13, neither provisional application teaches transfection with a polynucleotide encoding a degenerative protein as defined in paragraph 00084. Further, while the drawing filed in the provisional applications teaches that the engineered cells highly express HLA-DRA, the provisional applications do not teach that the engineered dendritic cells are transfected to express HLA-DRA, a MHC II protein primarily found on dendritic cells; see Bourdely et al. (Immunity. 53: 335-352: Published: August 18, 2020) page 337 right column.
Regarding claims 3, 10, and 15, the provisional applications only contemplate engineered dendritic cells targeting SAR-COV 2 proteins – not cytomegalovirus nor BK virus.
Regarding claim 13, the provisional application does not enable the method of producing the genetically engineered. More specifically, the provisional applications do not teach the growth factors of the first, second, or third culture medias, the steps of separating the 3-dimensional spheroid cells nor the iDCs, and, as mentioned above, the provisional applications do not teach transfecting with a vector comprising a polynucleotide encoding HLA-DR or HLA-DRA.
Regarding claim 20, the provisional applications do not teach using T cells not obtained from the patient.
Regarding claim 22, the provisional applications do not teach intravenous administration.
Accordingly, claims 1-23 are examined with priority to the actual filing date of May 25, 2023.
Should Applicant disagree with the above analysis, he/she may point to the precise locations of the teachings of the deficiencies noted above in U.S. Provisional Applications 63/365,327 and 63/366,127.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings are objected to because the text of Figure 4 is illegible. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is 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. See MPEP § 608.01.
Pages 56-57 citation numbers 1, 2, and 13 contain browser-executable code.
Claim Objections
Claims 5, 11, 13, 15, 16, and 17 are objected to because of the following informalities:
In claims 5 and 17, the word “the” or “said” should precede the word “protein” in line 2.
In claim 11 line 2, the word “vial” should be “viral”
In claim 13 steps (c) and (d), in order to avoid improper verb tense changes, the verbs “separate” in the first line of each step, and “culture” in the second line of each step should end in -ing (e.g. “separating the 3-dimenionsal spheroid […] and culturing said 3-dimenionsal spheroid”)
Claims 15-17 recite “wherein said protein” and ultimately depend from claim 13. While not indefinite because the mention of SARS-CoV 2 in claims 15-17 makes clear that the protein being referenced in claim 13 is the pathogenic protein of claim 13 step (e), BMP4, VEGF, and GM-CSF, for example, are also recited in claim 13 and are also proteins. Claims 15-17 would be more precise if “wherein said protein” in claim 13 were replaced with “wherein said pathogenic protein”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 5, 12, and 17 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 5, 12, and 17 depend from claims 4, 11, and 16 which recite that the protein is the SARS-CoV 2 spike protein or a fragment thereof. Claims 5, 12, and 17 recite that the protein is “at least one of the S1 and S2 subunit of SARS-CoV 2, or a fragment thereof.”
The spike protein consists of the S1 and S2 subunits; see Huang et al. (Acta Pharmacologica Sinica. 41: 1141-1149: Published: August 3, 2020) Abstract. Since the spike protein consists of the S1 and S2 subunits and claims 4, 11, and 16 recite a fragment thereof, claims 5, 12, and 17 fail to further limit claims 4, 11, and 16.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1-3, 6-10, 13-15, and 18-23 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.
Claim 1, from which all claims depend, recites the genera of engineered dendritic cells (DCs) comprising vectors comprising sequences encoding: pathogenic proteins, degenerative proteins, or fragments thereof and HLA-DR, HLA-DRA, or fragments thereof. Paragraphs 00083 and 00084 define “’pathogenic protein’ as a protein expressed on the surface of a pathogen, such as a virus, bacteria or other pathogenic or infectious agent” and “’degenerative protein’ a protein modifications that have been strongly implicated in the molecular pathogenesis of several age-related diseases affecting the cardiovascular system (CVS) and central nervous system (CNS), including atherosclerosis, heart disease, dementia syndromes, and stroke. Examples of degenerative proteins like amyloid beta and tau for Alzheimer's disease, and alpha-synuclein for Parkinson's disease.”
These definitions for pathogen or degenerative proteins are far from limiting and remarkably broad. For pathogenic protein, the definition encompasses a virus or bacteria, but also “other pathogenic or infectious agent[s]”. This option alone could encompass protozoa, fungi, parasitic worms, and even prions. For degenerative proteins, the definition is even more wide reaching. While the Specification exemplifies Alzheimer’s disease or Parkinson’s disease, degenerative proteins encompass far more. For example, age-related diseases affecting the CNS could include Amyotrophic Lateral Sclerosis (ALS), of which the cause is presently unknown, or Huntington's Disease (HD) caused by a mutated form of the Huntingtin (HTT) protein. Of CVS-affecting age-related diseases the Specification exemplifies atherosclerosis, heart disease, and stroke. These are all diseases associated with excessive deposits of atherosclerotic plaques, but these plaques are predominantly comprised of fatty acids or cholesterol – not a protein modification as defined. Liu et al. (Oxidative Medicine and Cellular Longevity. 2022: 3137329; Published: July 9, 2022) provides context for some protein modifications associated with cardiovascular disease. Reproduced below is Figure 3 from Liu et al. which highlights some protein modifications associated with atherosclerosis and hypertension, another age-related disease of the CVS.
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These modifications are merely posttranslational modifications and do not comprise genetic variants of proteins which may be implicated in atherosclerosis and hypertension, but provide context for expanse of mechanisms of pathogenesis in age-related CVS diseases. The possible degenerative protein link for all age-related CVS and CNS diseases is not as straightforward as amyloid beta and tau for Alzheimer's disease and alpha-synuclein for Parkinson's disease as exemplified in the Specification.
In contrast to the sweeping breadth of pathogenic and degenerative proteins claimed, Applicants have only described the use of 8 SARS-CoV-2 spike protein epitopes covalently linked to full-length HLA-DRA, understood to be the HLA-DR alpha chain. There is no single example in the Specification of engineered DCs comprising a vector encoding any other pathogenic or degenerative protein besides a SARS-CoV-2 spike protein epitope. Figure 11 describes “expos[ing] cytomegalovirus (CMV), and BK virus (BKV) proteins to our DC culture”, but this appears reference treating or applying some unspecified CMV or BKV proteins to the DCs engineered to comprise a vector encoding a SARS-CoV-2 spike protein epitope covalently linked to full-length HLA-DRA – not producing an engineered DC comprising a vector encoding a CMV or BKV epitope covalently linked to full-length HLA-DRA.
One of skill in the art would conclude that the applicant was not in possession of the claimed genera because a description of only one member of a single genus is not representative of the variants of the genera and is insufficient to support the claims.
Claims 21-23 are 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:
the method of treating a patient having a pathogen infection comprising administering the T cells previously co-cultured with the genetically engineered dendritic cell, wherein the genetically engineered dendritic cells comprise a vector comprising a polynucleotide sequence encoding a pathogenic protein thereof covalently linked to a HLA-DR or HLA-DRA, and
a T cell treatment preparation comprising pathogenic protein-specific T cells,
does not reasonably provide enablement for:
the method for treating a pathogen infection administering the T cells previously co-cultured with the genetically engineered dendritic cell, wherein the genetically engineered dendritic cells comprise a vector comprising a polynucleotide sequence encoding a degenerative protein and a HLA-DR or HLA-DRA,
the method for treating a pathogen infection administering the T cells previously co-cultured with the genetically engineered dendritic cell, wherein the genetically engineered dendritic cells comprise a vector comprising a polynucleotide sequence encoding a pathogenic protein and a HLA-DR or HLA-DRA, wherein the antigen (ie. SARS-COV-2 spike epitope) and the HLA class II molecule are not in the same open reading frame or covalently linked, and
a T cell treatment preparation comprising degenerative protein-specific T cells.
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 or use the invention commensurate in scope with these claims.
Claim 1, from which all claims depend, recites the genera of engineered dendritic cells (DCs) comprising vectors comprising sequences encoding: pathogenic proteins, degenerative proteins, or fragments thereof and HLA-DR, HLA-DRA, or fragments thereof. Paragraphs 00083 and 00084 define “’pathogenic protein’ as a protein expressed on the surface of a pathogen, such as a virus, bacteria or other pathogenic or infectious agent” and “’degenerative protein’ a protein modifications that have been strongly implicated in the molecular pathogenesis of several age-related diseases affecting the cardiovascular system (CVS) and central nervous system (CNS), including atherosclerosis, heart disease, dementia syndromes, and stroke. Examples of degenerative proteins like amyloid beta and tau for Alzheimer's disease, and alpha-synuclein for Parkinson's disease.”
These definitions for pathogen or degenerative proteins are far from limiting and remarkably broad. For pathogenic protein, the definition encompasses a virus or bacteria, but also “other pathogenic or infectious agent[s]”. This option alone could encompass protozoa, fungi, parasitic worms, and even prions. For degenerative proteins, the definition is even more wide reaching. While the Specification exemplifies Alzheimer’s disease or Parkinson’s disease, degenerative proteins encompass far more. For example, age-related diseases affecting the CNS could include Amyotrophic Lateral Sclerosis (ALS), of which the cause is presently unknown, or Huntington's Disease (HD) caused by a mutated form of the Huntingtin (HTT) protein. Of CVS-affecting age-related diseases the Specification exemplifies atherosclerosis, heart disease, and stroke. These are all diseases associated with excessive deposits of atherosclerotic plaques, but these plaques are predominantly comprised of fatty acids or cholesterol – not a protein modification as defined. Liu et al. (Oxidative Medicine and Cellular Longevity. 2022: 3137329; Published: July 9, 2022) provides context for some protein modifications associated with cardiovascular disease. Figure 3 from Liu et al. (see above) which highlights some protein modifications associated with atherosclerosis and hypertension, another age-related disease of the CVS.
These modifications are merely posttranslational modifications and do not comprise genetic variants of proteins which may be implicated in atherosclerosis and hypertension, but provide context for expanse of mechanisms of pathogenesis in age-related CVS diseases. The possible degenerative protein link for age-related CVS and CNS diseases is not as straightforward as amyloid beta and tau for Alzheimer's disease and alpha-synuclein for Parkinson's disease as exemplified in the Specification.
The nature of the invention is such that these genetically engineered dendritic cells may be co-cultured with T cells to educate CD4+ T cells by MHC class II antigen presentation. These educated T cells may then be infused into a patient to treat disease.
First, the covalent linkage between the antigen and the HLA class II molecule appears to be a critical feature of the claimed invention. Paragraph 0003 of the instant Specification states (emphasis added):
The DC-engineered viral constructs of the invention, including human leukocyte antigen - DR or DRA isotype (HLA-DR or HLA-DRA) covalently linked to the spike protein, or portions of the spike protein, including sub-units thereof, causes DCs to generate robust CD4+ and CDB+ T cells in patients regardless of race and ethnicity since HLA-DRA is found in 98% of the human population.3,4 Thus, the HLA-DRA combined spike protein of SARS-CoV-2 constructs of the invention produces a higher frequency of protective CD4+ T cells in clinical samples.
The art teaches that deficiencies in antigen processing in SARS-COV-2 infection and a reduction in MHC class II presentation were known to be part of the pathogenesis and a potential driver of immune evasion; see Nanaware et al. (The Journal of Immunology. 210: Supplement 1; Published: May 1, 2023). Similarly, variation in HLA molecules was understood to impact SARS-COV-2 epitope binding affinity; see Augusto et al. (Current Opinion in Immunology. 2022. 76: 102178; Published: March 25, 2022), and Charonis et al. (Journal of Immunological Sciences. 4(4): 12-23; Published: November 16, 2020). Thus, the covalent linkage between the SARS-COV-2 spike epitope and the HLA-DRA demonstrated in the Specification is a critical component of the invention. It is unpredictable whether an engineered dendritic cell comprising a vector merely comprising a polynucleotide sequence encoding a SARS-COV-2 spike protein and a second discrete polynucleotide sequence encoding the HLA-DR or HLA-DRA could produce protein-specific T cells or be used to treat SARS-COV-2 infection as required claims 18-23. Applicant has not demonstrated that genetically engineered dendritic cells comprising a vector encoding a SARS-COV-2 spike protein and an HLA-DR or HLA-DRA molecule not covalently linked can be used to sufficiently perform the methods of educating protein-specific T cells and treating infection by administering those T cells as claimed.
Second, the claimed invention encompasses genetically engineered dendritic cells comprising a vector encoding any pathogenic or degenerative protein. As discussed above this is an incredibly broad category of proteins. Claims 21-22 recite a method of treating “pathogenic infection” and claim 23 reciting a “T cell treatment preparation” indicates intended use to treat a disease – not limited to a pathogenic infection. Claims 21 and 22 reference claim 18 which recites a method of generating a protein-specific T cell population by coculturing T cells with dendritic cells comprising a vector encoding a pathogenic or degenerative protein and a HLA-DR or HLA-DRA. It is unclear how a T cell stimulated from a dendritic cells presenting a degenerative protein can be used to treat a pathogenic infection.
Further, regarding degenerative diseases, there’s no indication in the Specification, from experiments restricted to the presentation of a SARS-COV-2 spike protein that these genetically engineered dendritic cells can be applied to treat any age-related disease affecting the CVS or CNS. At best, the instant Specification merely provides the idea that one could use genetically engineered dendritic cells to educate T cells to be used for the treatment any age-related disease affecting the CVS or CNS.
Regarding age-related diseases affecting the CNS, Harms et al. (The Journal of Neuroscience. 33(23): 9592-9600; Published: June 5, 2013) and Subbarayan et al. (Journal of Neuroinflammation. 17: 242; Published: August 15, 2020) teach that MHC II upregulation and T cell infiltration leads to increased neuronal loss. Thus, contrary to the suggested, but not validated, use of the genetically engineered dendritic cells to form a T cell treatment for Parkinson’s disease in the Specification, it is unpredictable whether such a T cell treatment could be used in Parkinson’s disease.
In order to make and use the invention in accordance with the scope of the claims, one would have to identify pathogenic and degenerative proteins and epitopes or fragments thereof, produce the genetically engineered dendritic cells, coculture those DCs with T cells, and validate their efficiency in an immune competent animal model of a representative number of species of age-related diseases affecting the CVS and CNS. As discussed above, the “protein modifications that have been strongly implicated in the molecular pathogenesis of several age-related diseases affecting the cardiovascular system (CVS) and central nervous system (CNS)” or degenerative proteins associated the age-related diseases have yet to be elucidated. Thus, in order to make or use the claimed invention for some diseases, one would first have to discover a degenerative protein “strongly implicated in the molecular pathogenesis”.
Considering the unpredictability, the high level of skill, and the limited direction provided by the inventor, it would take more than reasonable experimentation to make or use the invention commensurate in scope with the claims.
Claim Rejections - 35 USC § 102
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 8 and 9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhu et al. (European Journal of Immunology. 27(8): 1933-1941; Published: August 1997).
Claims 8 and 9 recite a polynucleotide construct comprising a sequence encoding a pathogenic or degenerative protein or fragment thereof and a sequence encoding HLA-DR or HLA-DRA or a fragment thereof and wherein the pathogenic protein is a viral surface of membrane protein.
Zhu et al. teaches a polynucleotide construct encoding HIV GAG or influenza hemagglutinin covalently bound to a single chain HLA-DR molecule; see Sections 2.3, 2.4, and 2.5.
Thus, Zhu et al. anticipates claims 8 and 9.
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 1-2, 6, 8, 9, and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Zhu et al. (European Journal of Immunology. 27(8): 1933-1941; Published: August 1997) and Decker et al. (US 2018/0127717 A1; Published: May 10, 2018).
Regarding the vector or polynucleotide comprising HLA-DR and a pathogenic protein in claims 1-2, 6, 8, 9, Zhu et al. teaches an HLA-DR molecule covalently linked to an antigenic peptide, including influenza hemagglutinin or HIV p24 gag which are viral surface or membrane proteins; see sections 2.3 – 2.5. Zhu et al. teaches transfecting mouse DAP3 L cells to express the HLA-DR – antigenic peptide fusion; see section 2.6. Zhu et al. teaches that the HLA-DR – antigenic peptide fusion expressing cells were co-cultured with T cells resulting in DR-restricted antigenic peptide-specific T cells; see sections 2.10 and 3.6. Additionally, Zhu et al. teaches that the alpha chain (ie. HLA-DRA) engages directly with T cell antigen receptors; see last paragraph.
Zhu et al. does not teach an engineered dendritic cell to stimulate T cells.
Regarding dendritic cells expressing a pathogenic protein in claims 1-2, 6, Decker et al. teaches loading or priming dendritic cells to recombinantly express antigens, including antigens associated with infectious disease; see claims 23 and 24 and Examples 1 and 3. Regarding claims 18-20, and similar to Zhu et al., Decker et al. teaches co-culturing the primed dendritic cells with T cells for ex vivo expansion of antigen-specific T cells; see claims 37-40 and 77-80. Regarding the source of the T cells to be co-cultured in claims 19 and 20, Decker et al. teaches that partially HLA matched dendritic cells loaded with antigens can stimulate T cells; see paragraph 0039. Note that “a patient” in claim 19 is interpreted as any patient and not limited to a patient to be treated with said protein-specific T cells.
It would have been obvious to one or ordinary skill in the art and one would have had a reasonable expectation of success to engineer a dendritic cell to recombinantly express a MHC molecule covalently linked to the antigen. One would have been motivated to express the HLA-DR linked to a pathogenic protein in a dendritic cell because Decker et al. teaches that dendritic cells are “most highly specialized in antigen processing and presentation, lymphocyte co-stimulation, and the generation of cytokines and other inflammatory mediators that modulate terminal T-cell differentiation” (see paragraph 0005) and recombinant expression of the antigen linked to the MHC class II molecule reduces the variability of the epitopes naturally processed and presented and improves the reproducibility.
Finally, regarding coculturing T cells with the engineered dendritic cells, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to do so because Zhu et al. demonstrates that the HLA – antigen construct is capable of stimulating T cells and Decker et al. teaches that dendritic cells loaded with antigen can be used to produce antigen-specific T cells following coculture. Regarding the source of the T cells for coculture, Decker et al. teaches that partially-HLA matched dendritic cells were able to stimulate T cell response; see paragraph 0039. Additionally, of the embodiment in Decker et al. wherein dendritic cells are to be administered to a subject for the method of generating an immune response, Decker et al. teaches that the dendritic cells may be from the subject to be treated, from a HLA-matched donor, or a bank defined by HLA-typing. Thus, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success using T cells from a patient or from a patient not to be treated so long as the dendritic cells and T cells to be cocultured together are a HLA-match.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 3-5 and 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Zhu et al. (European Journal of Immunology. 27(8): 1933-1941; Published: August 1997) and Decker et al. (US 2018/0127717 A1; Published: May 10, 2018) as applied to claim(s) 1-2, 6, 8, 9, and 18-20 above, and further in view of Nanaware et al. (The Journal of Immunology. 210: Supplement 1; Published: May 1, 2023) and as evidenced by Huang et al. (Acta Pharmacologica Sinica. 41: 1141-1149: Published: August 3, 2020).
The teachings of Zhu et al. and Decker et al. as related to claim(s) 1-2, 6, 8, 9, and 18-20, from which these claims depend are given previously in this Office action and are fully incorporated here.
While Zhu et al. teaches using a viral surface or membrane protein, the reference does not teach a SARS-COV-2 surface or membrane protein nor a SARS-COV-2 spike protein.
Regarding targeting viral surface or membrane proteins associated with SARS-COV-2, Nanaware et al. teaches identifying naturally processed and presented MHC-II molecules, including HLA-DR, bound to spike proteins. Regarding the S1 and S2 subunits, Huang et al. (Acta Pharmacologica Sinica. 41: 1141-1149: Published: August 3, 2020) evidences that the spike protein consists of the S1 and S2 subunits; see Abstract. Further, Nanaware et al. teaches that a downregulation of surface and total HLA-ABC, HLA-DR and HLA-DP expression upon SARS-COV-2 infection was observed in addition to a significant downregulation of proteins involved in antigen processing and MHC loading, including CD74, CIITA, and cathepsins.
Given that Nanaware et al. teaches that SARS-COV-2 immune evasion is associated with downregulation of HLA-DR and CIITA, a protein which processes antigens for MHC class II display, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to modify the HLA-DR – antigenic peptide construct taught by Zhu et al. to comprise a spike or membrane protein of SARS-COV-2 as taught by Nanaware et al. One would have been motivated to covalently link the MHC class II molecule and antigen because of observed deficiencies in CIITA and MHC antigen loading.
Furthermore, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to express the HLA-DR – SARS-COV-2 spike fusion in a dendritic cell. One would have been motivated to express the HLA-DR – SARS-COV-2 spike fusion in a dendritic cell because Nanaware et al. teaches that antigen processing and presentation is deficient in SARS-COV-2 infection. A covalently linked antigen bypasses antigen processing to artificially present the antigen and a dendritic cell engineered to express the HLA-DR – SARS-COV-2 spike fusion could be used to study the potential of a dendritic cell-based vaccine.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over Zhu et al. (European Journal of Immunology. 27(8): 1933-1941; Published: August 1997) and Decker et al. (US 2018/0127717 A1; Published: May 10, 2018) as applied to claim(s) 1-2, 6, 8, 9, and 18-20 above, and further in view of Latouche et al. (US 2018/0355316 A1; Published: December 13, 2018).
The teachings of Zhu et al. and Decker et al. as related to claim(s) 1-2, 6, 8, 9, and 18-20, from which these claims depend are given previously in this Office action and are fully incorporated here.
Neither Zhu et al. nor Decker et al. teaches teaching infection comprising administering protein-specific T cells.
Similar to Decker et al., Latouche et al. teaches amplifying antigen-specific memory CD4+ T cells comprising co-culturing T cells with artificial antigen presenting cells stably transfected to express an MHC class II molecule, including HLA-DR, and loaded or treated with an antigen, including a viral antigen; see claims 1, 4, 5, 12, and 16. Further, regarding the method of treating an infection comprising administering the protein-specific T cells in claim 21, Latouche et al. teaches a method of treating infectious disease comprising administering a therapeutically effective amount of antigen-specific memory CD4+ T cells; see claim 17. Regarding claims 22 and 23, Latouche et al. teaches collecting the antigen-specific T cells in a medium or container system suitable for administration or comprising a pharmaceutically acceptable carrier and intravenous administration; see paragraphs 0057-0058.
It would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success because Latouche et al. teaches treating infection with antigen-specific CD4+ T cells expanded ex vivo. One would have been motivated to administer the antigen-specific CD4+ T cells expanded ex vivo as taught by Latouche et al. as opposed to administered engineered dendritic cells as taught by Decker et al. because the dendritic cells require site specific administration for best efficacy.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Zhu et al. (European Journal of Immunology. 27(8): 1933-1941; Published: August 1997) and Decker et al. (US 2018/0127717 A1; Published: May 10, 2018) as applied to claim(s) 1-2, 6, 8, 9, and 18-20 above, and further in view of Sachamitr et al. (Frontiers in Immunology. 8:1935; Published: January 8, 2018).
The teachings of Zhu et al. and Decker et al. as related to claim(s) 1-2, 6, 8, 9, and 18-20, from which these claims depend are given previously in this Office action and are fully incorporated here.
While Decker et al. teaches culturing dendritic precursor cells (see paragraphs 00045-00052), the reference does not teach steps (a) – (d) of claim 13 or producing dendritic cells from human iPSCs.
Sachamitr et al. teaches culturing human iPSCs to generate mature dendritic cells
Given that Decker et al. teaches that primed dendritic cells generated from dendritic cell precursors are suitable for generating an immune response or stimulating T cells and since Sachamitr et al. teaches that mature dendritic cells can be cultured from human iPSCs, it would have been obvious to one of ordinary skill in the art to induce dentritic cells from human iPSCs to be engineered to express the HLA-DR – antigen fusion.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 13 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Zhu et al. (European Journal of Immunology. 27(8): 1933-1941; Published: August 1997) and Decker et al. (US 2018/0127717 A1; Published: May 10, 2018), in view of Sachamitr et al. (Frontiers in Immunology. 8:1935; Published: January 8, 2018) and Michiels et al. (Gene Therapy. 12: 772-782; Published: March 3, 2005).
The teachings of Zhu et al. and Decker et al. are given previously in this Office action and are fully incorporated here.
While Decker et al. teaches culturing dendritic precursor cells (see paragraph 00052), the reference does not teach steps (a) – (d) of claim 13 or producing dendritic cells from human iPSCs.
Sachamitr et al. teaches culturing human iPSCs in media supplemented with BMP4, VEGF, SCF, GM-CSF; see (B) on page 8. Sachamitr et al. teaches adding additional BMP4, VEGF, SCF, and GM-CSF; see (C) on pages 8-9. Sachamitr et al. teaches separarting the 3-dimensional spheroid cells, referred to as embryoid bodies in Sachamitr et al., and resuspending the cells in fresh media comprising IL-4; see (D)(1)-(D)(3) on page 9. Finally, Sachamitr et al. teaches harvesting immature DCs and culturing them in media supplemented with GM-CSF, IL-4, TNF-α, IFN-γ, PGE2, and IL-1β; see (E) on pages 9-10.
Sachamitr et al. does not teach transfecting mature dendritic cells.
Michiels et al. teaches that transfecting dendritic cells in their mature differentiation state yields a greater proportion of cells expression co-stimulatory molecules compared to dendritic cells electroporated in their immature differentiation state; see Figure 3.
It would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to combine the differentiation and maturation protocol of Sachamitr et al. with the teachings of Michiels et al. regarding transfecting mature dendritic cells in order to produce the dendritic cells comprising a vector comprising HLA-DR and a pathogenic protein as taught by Zhu et al. and Decker et al. One would have been motivated to transfect mature dendritic cells because Michiels et al. teaches that dendritic cells transfected in their mature differentiation state express more co-stimulatory molecules which are needed for the ex vivo expansion of antigen-specific T cells as taught by Decker et al.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the application, as evidenced by the references.
Claims 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Zhu et al. (European Journal of Immunology. 27(8): 1933-1941; Published: August 1997) and Decker et al. (US 2018/0127717 A1; Published: May 10, 2018), in view of Sachamitr et al. (Frontiers in Immunology. 8:1935; Published: January 8, 2018) and Michiels et al. (Gene Therapy. 12: 772-782; Published: March 3, 2005). as applied to claim(s) 13 and 14 above, and further in view of Nanaware et al. (The Journal of Immunology. 210: Supplement 1; Published: May 1, 2023) and as evidenced by Huang et al. (Acta Pharmacologica Sinica. 41: 1141-1149: Published: August 3, 2020).
The teachings of Zhu et al. and Decker et al. in view of Sachamitr et al. and Michiels et al. as related to claim(s) 13 and 14, from which these claims depend are given previously in this Office action and are fully incorporated here.
While Zhu et al. teaches using a viral surface or membrane protein, the reference does not teach a SARS-COV-2 surface or membrane protein nor a SARS-COV-2 spike protein.
Regarding targeting viral surface or membrane proteins associated with SARS-COV-2, Nanaware et al. teaches identifying naturally processed and presented MHC-II molecules, including HLA-DR, bound to spike proteins. Regarding the S1 and S2 subunits, Huang et al. (Acta Pharmacologica Sinica. 41: 1141-1149: Published: August 3, 2020) evidences that the spike protein consists of the S1 and S2 subunits; see Abstract. Further, Nanaware et al. teaches that a downregulation of surface and total HLA-ABC, HLA-DR and HLA-DP expression upon SARS-COV-2 infection was observed in addition to a significant downregulation of proteins involved in antigen processing and MHC loading, including CD74, CIITA, and cathepsins.
It would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to express the HLA-DR – SARS-COV-2 spike fusion in a dendritic cell derived from human iPSCs from the method of instant claim 13. One would have been motivated to express the HLA-DR – SARS-COV-2 spike fusion in a dendritic cell because Nanaware et al. teaches that antigen processing and presentation is deficient in SARS-COV-2 infection. A covalently linked antigen bypasses antigen processing to artificially present the antigen and a dendritic cell engineered to express the HLA-DR – SARS-COV-2 spike fusion could be used to study the potential of a dendritic cell-based vaccine.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure: Silk et al. (US 9,598,674 B2; Published: March 21, 2017) teaches a method of producing dendritic cells from iPSCs; see column 19. Saito et al. (Journal of Virology. 82(7): 3320-3328; Published: January 23, 2008) teaches that HCV downregulates surface expression of HLA-DR.
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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682