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 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, 4-8, 11-13, and 16-23 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.
Claim Objections
Claim 17 is objected to because of the following informalities:
In claim 17, the word “the” or “said” should precede the limitation “viral antigen” in lines 1-2.
Appropriate correction is required.
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, 4, 6, 8, 9, 11, 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) in view of Decker et al. (US 2018/0127717 A1; Published: May 10, 2018) and 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).
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.
Regarding claims 8 and 9, which 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.
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.
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 the SARS-COV-2 spike protein in claims 1, 8, and 13, 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 extracellular portion of 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 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-DRA linked to a viral antigen or degenerative disease-associated peptide 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.
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-DRA – 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-DRA – SARS-COV-2 spike fusion in a dendritic cell. One would have been motivated to express the HLA-DRA – 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-DRA – 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) in view of Decker et al. (US 2018/0127717 A1; Published: May 10, 2018) and 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) as applied to claim(s) 1-2, 4, 6, 8, 9, 11, 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. in view of Decker et al. and Nanaware et al. and as evidenced by Huang et al. as related to claim(s) 1-2, 4, 6, 8, 9, 11, 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) in view of Decker et al. (US 2018/0127717 A1; Published: May 10, 2018) and 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) as applied to claim(s) 1-2, 4, 6, 8, 9, 11, 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. in view of Decker et al. and Nanaware et al. and as evidenced by Huang et al. as related to claim(s) 1-2, 4, 6, 8, 9, 11, 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.
Claim 13 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) in view of Decker et al. (US 2018/0127717 A1; Published: May 10, 2018) and Nanaware et al. (The Journal of Immunology. 210: Supplement 1; Published: May 1, 2023), 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), and as evidenced by Huang et al. (Acta Pharmacologica Sinica. 41: 1141-1149: Published: August 3, 2020).
The teachings of Zhu et al. in view of Decker et al. and Nanaware et al. and as evidenced by Huang 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.
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.
Claims 5 and 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) in view of Decker et al. (US 2018/0127717 A1; Published: May 10, 2018) and 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) as applied to claim(s) 1-2, 4, 6, 8, 9, 11, and 18-20 above, and further in view of Kim et al. (Vaccines. 9: 316; Published: March 29, 2021).
The teachings of Zhu et al. in view of Decker et al. and Nanaware et al. and as evidenced by Huang et al. as related to claim(s) 1-2, 4, 6, 8, 9, 11, and 18-20, from which these claims depend are given previously in this Office action and are fully incorporated here.
Claims 16 and 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) in view of Decker et al. (US 2018/0127717 A1; Published: May 10, 2018), Nanaware et al. (The Journal of Immunology. 210: Supplement 1; Published: May 1, 2023), 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), and as evidenced by Huang et al. (Acta Pharmacologica Sinica. 41: 1141-1149: Published: August 3, 2020), as applied to claim(s) 13 above, and further in view of Kim et al. (Vaccines. 9: 316; Published: March 29, 2021).
The teachings of Zhu et al. in view of Decker et al., Nanaware et al., Sachamitr et al., and Michiels et al., and as evidenced by Huang et al., as related to claim(s) 13, from which these claims depend are given previously in this Office action and are fully incorporated here.
The following analysis applies to both the rejections of claims 4, 5, 11, and 12; and 16 and 17 above.
Neither Zhu et al., Decker et al., Nanaware et al., Sachamitr et al., Michiels et al., nor Huang et al. teach an HLA-DRA polypeptide in a fusion protein with a full-length spike protein nor a full-length S1 or S2 subunit.
Kim et al. teaches that both the S1 and S2 subunits are similarly immunogenic; see page 12 top paragraph. Further, Kim et al. teaches that the number of stimulated IFN-gamma positive T cells were higher in mice immunized with full-length spike protein compared to mock control mice, indicating that T cell responses to full length spike protein were generated; see Figure 6.
Given that Kim et al. teaches that both the S1 and S2 subunits are equally immunogenic and that T cell responses can be raised against full-length spike protein, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to make a polynucleotide construct or a dendritic cell comprising a vector comprising the full-length spike protein (consisting of S1 and S2) in a fusion protein with HLA-DRA as taught by Zhu et al. in view of Decker et al., and Nanaware et al., or Zhu et al. in view of Decker et al., Nanaware et al., Sachamitr et al., and Michiels et al. One would have been motivated to use the full-length spike protein because Kim et al. teaches that the S1 and S2 subunits are equally immunogenic and that full-length spike and S1 subunit immunization induced higher levels of neutralizing antibodies; see page 12.
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.
Response to Arguments
Applicant’s amendments filed June 9, 2026 are acknowledged. Any rejection not repeated above is resolved by amendment.
Regarding the rejections under 35 U.S.C. 112(a), Applicant has narrowed the claims to recite the viral antigens or degenerative disease-associated peptides selected from SARS-CoV-2 S1, SARS-CoV-2 S2, amyloid-beta, tau, alpha-synuclein, and fragments thereof. While the fragments thereof is broad, there is description in the prior art of immunogenic fragments of these proteins; see Ghochikyan et al. (Neuroscience Letters. 560: 86-91; Published: February 7, 2014), Guo et al. (Ageing and Neurodegenerative Diseases. 2: 11; Published: July 22, 2022), Joly-Amado et al. (Neurobiology of Disease. 134: 104636; Published Online: October 17, 2019), Mantile et al. (Biology. 9: 0425; Published: November 27, 2020), Roda et al. (Neural Regeneration Research. 17(8): 1666-1674; Published Online: January 7, 2022), and Yu et al. (Movement Disorders. 37(7): 1416-1424; Published Online: August 17, 2021). Given the description of immunogenic fragments of SARS-CoV-2 S1, SARS-CoV-2 S2, amyloid-beta, tau, and alpha-synuclein, one of ordinary skill in the art could make or use the claimed inventions commensurate with their scope with only reasonable amount of experimentation. The rejections under 35 U.S.C. 112(a) are overcome by amendment.
Regarding the rejections under 35 U.S.C. 103, on page 9, Applicant argues that Zhu et al. does not relate to engineered dendritic cells.
Zhu et al. does not teach engineered dendritic cells, but rather the vector encoding the antigen in a fusion protein with HLA-DRA. However, Decker et al. teaches loading or priming dendritic cells to recombinantly express antigens, including antigens associated with infectious disease; see section 103 above.
On page 10, Applicant argues that Decker et al. does not teach T cell education or expansion which is the key therapeutic outcome.
Decker et al. does teach co-culturing T cells with loaded antigen presenting cells for the ex-vivo expansion of antigen specific T cells; see section 103 above or Decker claims 37 and 38. Regarding Applicant’s arguments to therapeutic outcome, the claims to method of treating are claims 21-23 and are addressed further in view of Latouche et al. which teaches administering the ex vivo expended T cells in a method of treating; see section 103.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
On page 11, Applicant argues the Nanaware et al. teaches that SARS-CoV-2 suppresses MHC II and that the fusion construct is not obvious. Applicant argues impermissible hindsight.
The Office disagrees. As stated above, Nanaware et al. teaches the SARS-CoV-2 is associated with deficiencies in MHC II loading. It would have been obvious to one of ordinary skill in the art to modify the construct taught by Zhu et al. to comprise a spike protein fragment because of the known MHC II loading deficiencies.
Regarding hindsight, “’[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper.’ In re McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971).”; see MPEP 2145 X.A. All facts and rationale provided in the rejections above were available to one of ordinary skill in the art prior to the effective filing date.
Conclusion
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.
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
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