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 .
Claim Status
Claims 1-18 and 20 are cancelled. Claims 19 and 21-30 as filed on 08 July 2026 are pending and under examination.
Rejections Withdrawn
Rejection of claims 1-4, 12, 14, 17-18, and 20 under 35 U.S.C. 101 is withdrawn with applicant amendment to claims.
Rejection of claim 14 under 35 U.S.C. 112(b) is withdrawn with cancellation of claim.
The objection of claim 16 is withdrawn with applicant amendment of claims.
Rejection of claims 1-9, 12-14, 16-20 under 35 U.S.C. 102 is withdrawn with applicant amendment of claims where claims were cancelled and claim 19 is amended to a new patient population requiring a new search and new grounds of rejection.
The rejection of claims under Double Patenting over US 11866731 B2 and Copending application 19107364 is withdrawn with applicant amendment of claims.
New Rejection Necessitated by Applicant Amendment to Claims
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(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 19, 22-23, 25-26, and 29 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Festag et. al. Molecular Therapy. 27(5):947-959. (2019) (PTO-892), as evidenced by Nittoli (US 20160354482 A1) (PTO-892).
Regarding claims 19 and 25-26, Festag teaches Hepatitis B Virus specific CAR T for administration in the treatment of chronic viral infection (Abstract). Festag teaches the S-CAR of the invention comprises and scFv in the extracellular domain and an intracellular domain with a signaling domain (page 947 in col 2 in par 1). Festag teaches the administration to a mouse model for chronic HBV infection (Figure 1). Festag teaches the S-CAR T cells were PD-1 positive (page 951 in col 1 in par 1).
Regarding claim 27, Festag teaches the production of the S-CAR that binds HBV cells with functional intracellular T cell signaling domains and the SΔ-CAR T cells where the extracellular binding domain is the same but the intracellular T cell signaling domains are not present (page 948 in col 2 in par 2).
Regarding claim 22, the claims is to a method of treatment where the extracellular domain (ECD) of the CAR comprises an antibody, a ligand, and a fragment or portion of the receptor. There is definition required in the specification for ligand, fragment, or portion. A fragment or portion of a receptor would include a single amino acid of a receptor the scFv of the CAR of Festag comprises multiple amino acids present in receptors. A ligand is a molecule or compound that specifically binds to a second molecule or compound and includes antibodies, as evidenced by Nittoli ([0111]). Festag teaches the ECD of the S-CAR binds the envelope protein of HBV (abstract). The scFv would then comprise a fragment or portion of a receptor, an antibody, and a ligand by reciting an scFv in the CAR.
Regarding claim 23, Festag teaches the CAR intracellular domain of CD28 (page 949 in col 2 in par 1 in last line 2 lines of paragraph).
Regarding claim 29, Festag teaches the CAR T cells should comprise further safeguards to be able to deplete T cells if needed (page 947 in col 2 in par 1).
Claim Rejections - 35 USC § 103
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.
Claims 19, 21, and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Kruse et. al. Cytotherapy. 20:697-705 (2018) (PTO-892) and Festag et. al. Molecular Therapy. 27(5):947-959. (2019) (PTO-892).
Kruse teaches a mouse model of viral infection of chronic HBV infection with CAR T cells that bind HBV infected cells. Kruse teaches a decrease in plasma levels of HBV in plasma when compared to control (Abstract). Kruse teaches the CAR comprises an HBV specific ECD and an intracellular domain (page 698 in col 1 in par 1 and page 699 in col 2 in par 1). Kruse teaches limited efficacy in not reducing the number of HBV-infected hepatocytes in the mouse model (abstract and page 701 in col 2 in par 2). Kruse further teaches future studies of characterizing the phenotype of the HBV binding CAR T cells for exhaustion markers including PD-1 (page 703 in col 1 in lines 1-7).
Regarding claim 21, Kruse teaches the CAR T cells were generated from PBMCs (page 698 in col 2 in par 1).
Regarding claim 27, Kruse teaches the CAR of the modified immune cells bind a different antigen than the TCR of the cells as modified immune cells not comprising the CAR did not bind the HBV cells and additionally changes to the length of the spacer in the HBV specific CAR improved binding (Figure 1 A and C).
Kruse does not teach the CAR T cells are PD-1 positive.
This deficiency is filled by Festag.
Festag teaches Hepatitis B Virus specific CAR T for administration in the treatment of chronic viral infection (Abstract). Festag teaches the S-CAR of the invention comprises and scFv in the extracellular domain and an intracellular domain with a signaling domain (page 947 in col 2 in par 1). Festag teaches the administration to a mouse model for chronic HBV infection (Figure 1). Festag teaches the S-CAR T cells were PD-1 positive (page 951 in col 1 in par 1).
It would have been obvious at the time the application was filed to combine the HBV binding CAR T cells for use in a method of treating chronic Hepatitis C infection with the PD-1+ CAR T cells of Festag where the PD-1+ CAR T cells bind HBV and are used in a method of treating chronic Hepatitis C infection. One of skill in the art would have been motivated at the time the application was filed by the teaching of Kruse that the not fully effective CAR T cells of their method could be improved by considering markers including PD-1 and Festag teaches PD-1+ CAR T cells for targeting HBV. There would have been a reasonable expectation of success as Kruse teaches towards considering PD-1 expression on CAR T cells for use in their method and Festag teaches PD-1+ CAR T cells for use in targeting HBV and Kruse and Festag both teach CAR T cells for use in chronic hepatitis B infection.
Claims 19 and 22-24 are rejected under 35 U.S.C. 103 as being unpatentable over Festag et. al. Molecular Therapy. 27(5):947-959. (2019) (PTO-892), Yang et. al. Journal American Chemical Society. 142(44):18874–18885. (2020) (Published 09/23/2020) (PTO-892), and Yang et. al. Molecular Therapy – Oncolytics. (17):571-585. (2020) (“Yang 2020” PTO-892), as evidenced by Nittoli (US 20160354482 A1) (PTO-892).
Regarding claim 19, Festag teaches Hepatitis B Virus specific CAR T for administration in the treatment of chronic viral infection (Abstract). Festag teaches the S-CAR of the invention comprises and scFv in the extracellular domain and an intracellular domain with a signaling domain (page 947 in col 2 in par 1). Festag teaches the administration to a mouse model for chronic HBV infection (Figure 1). Festag teaches the S-CAR T cells were PD-1 positive (page 951 in col 1 in par 1).
Regarding claim 22, the claims is to a method of treatment where the extracellular domain (ECD) of the CAR comprises an antibody, a ligand, and a fragment or portion of the receptor. There is definition required in the specification for ligand, fragment, or portion. A fragment or portion of a receptor would include a single amino acid of a receptor the scFv of the CAR of Festag comprises multiple amino acids present in receptors. A ligand is a molecule or compound that specifically binds to a second molecule or compound and includes antibodies, as evidenced by Nittoli ([0111]). Festag teaches the ECD of the S-CAR binds the envelope protein of HBV (abstract). The scFv would then comprise a fragment or portion of a receptor, an antibody, and a ligand by reciting an scFv in the CAR.
Regarding claim 23, Festag teaches the CAR intracellular domain of CD28 (page 949 in col 2 in par 1 in last line 2 lines of paragraph).
Festag does not teach an scFv that binds PD-L1 as part of the PD1+ CAR T Cell.
This deficiency is filled by Yang and Yang 2020.
Yang teaches checkpoint blocking therapy that blocks inhibitory T cell signal pathway. Yang teaches that PD1+ CAR T cells in combination with a PD1/PD-L1 pathway improves efficacy of the CAR T cell therapy (abstract and page 18874 in col 2 in par 1). Yang teaches the presence of a PD-L1 blocking peptide including PD-1 (Figure 1).
Yang 2020 teaches CAR T cell that comprises a PD-L1 binding peptide showing the PD-1 and an anti-PD-L1 scFv both bind PD-1 as a component of a CAR T cell (abstract and Figure 1).
It would have been obvious at the time the application was filed to combine the therapeutic PD1+ S-CAR for use in a method of treatment of Festag with the PD-1 binding component of Yang and Yang 2020 to produce a PD1+ S-CAR comprising an scFV binding PD-L1. One of skill in the art would have been motivated by Yang’s teaching of a PD-L1 blocking peptide on a PD1+ CAR T cell to evade inhibitory T cell signaling. A PD-1 binding PD-L1 and a PD-L1 binding scFv would be art equivalents making their substitution obvious as shown by Yang 2020. There would have been a reasonable expectation of success as Yang teaches improved therapeutic use with PD1+ CAR T cells that comprise a PD-L1 binding peptide.
Claims 19 and 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over Festag et. al. Molecular Therapy. 27(5):947-959. (2019) (PTO-892) and Sadelain et. al. Cancr Discov. 3(4):388-398 (2013) (PTO-892).
Regarding claim 19, Festag teaches Hepatitis B Virus specific CAR T for administration in the treatment of chronic viral infection (Abstract). Festag teaches the S-CAR of the invention comprises and scFv in the extracellular domain and an intracellular domain with a signaling domain (page 947 in col 2 in par 1). Festag teaches the administration to a mouse model for chronic HBV infection (Figure 1). Festag teaches the S-CAR T cells were PD-1 positive (page 951 in col 1 in par 1).
Regarding claim 29, Festag teaches the CAR T cells should comprise further safeguards to be able to deplete T cells if needed (page 947 in col 2 in par 1).
Festag does not teach the modified immune cell comprises a suicide switch.
This deficiency is filled by Sadelain.
Sadelain teaches improving CAR safety by limiting or preventing off-target effects and cytokines storms by including a suicide genes that can be used to eliminate CAR to prevent excessive response (page 394 in col 2 in final par).
It would have been obvious at the time the application was filed to substitute the generic mechanism of safeguard to deplete the T cells of Festag with the suicide genes of Sadelain. One of skill in the art would have been motivated by the teaching of Festag that the CAR T cells need a safeguard to deplete T cells if needed and Festag teaches limiting or preventing off-target effects and cytokines storms by including a suicide genes. It would have been an obvious substitution of a generic mechanism to deplete CAR T cells with the specific suicide genes of Sadelain. There is a reasonable expectation of success as Festag and Sadelain are both teaching CAR T cells that comprise a mechanism to deplete excessive T cells.
Claims 19 and 27-28 are rejected under 35 U.S.C. 103 as being unpatentable over Kruse et. al. Cytotherapy. 20:697-705 (2018) (PTO-892) and Festag et. al. Molecular Therapy. 27(5):947-959. (2019) (PTO-892) as applied to claims 19, 21, and 27 above, and further in view of Tout et. al. The Journal of Immunology. 201(8):2331-2344. (2018) (PTO-892) and Walsh et. al. Current Hematologic Malignancy Reports. 14:451-459 (2018) (PTO-892).
The teachings of Kruse from the previous 103 art rejections are incorporated here in full.
Kruse teaches a mouse model of viral infection of chronic HBV infection with CAR T cells that bind HBV infected cells. Kruse teaches a decrease in plasma levels of HBV in plasma when compared to control (Abstract). Kruse teaches the CAR comprises an HBV specific ECD and an intracellular domain (page 698 in col 1 in par 1 and page 699 in col 2 in par 1). Kruse teaches limited efficacy in not reducing the number of HBV-infected hepatocytes in the mouse model (abstract and page 701 in col 2 in par 2). Kruse further teaches future studies of characterizing the phenotype of the HBV binding CAR T cells for exhaustion markers including PD-1 (page 703 in col 1 in lines 1-7).
Regarding claim 27, Kruse teaches the CAR of the modified immune cells bind a different antigen than the TCR of the cells as modified immune cells not comprising the CAR did not bind the HBV cells and additionally changes to the length of the spacer in the HBV specific CAR improved binding (Figure 1 A and C).
The teachings of Festag from the previous 103 art rejections are incorporated here in full.
Kruse and Festag teaches a method of treating chronic HBV infection by administering a PD1+ CAR T cell comprising an ECD that binds HBV infected cells as previously described.
Kruse does not teach the CAR T cells binds CD19.
This deficiency is filled by Tout and Walsh.
Tout teaches adult and pediatric patients worldwide developing chronic HBV infection and are at high risk of serious complications including liver cirrhosis (page 2231 in col 1 in par 1). Tout teaches CD19 positive B cells infected with HBV (Figure 3).
Walsh teaches multi-specific CAR therapy targeting B cells (Abstract and Figure 1) and specifically teaches CD19 binding CAR T cells that bind CD19+ B cells only when the second disease antigen is present (Figure 1 and page 454 in col 1 in par 1-2).
It would have been obvious at the time the application was filed to combine the Kruse and Festag teaches a method of treating chronic HBV infection by administering a PD1+ CAR T cell comprising an ECD that binds HBV infected cells with the CD19 bispecific CAR T of Walsh in view of Tout to produce a CAR T cell that binds B cells infected with HBV in cases of chronic HBV infection. One of skill in the art would have been motivated by the teachings of Tout to target HBV infected B cells. There would have been a reasonable expectation of success as Kruse and Festag teach the targeting of HBV infected cells using CAR T cells and Tout teaches CD19 B cells infected by HBV and bispecific CAR T cells that bind CD19 and a second disease antigen are well known in the art.
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.
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/F.E./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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