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 .
Status of Claims / Response to Amendment
The Amendments and Remarks filed 01/02/2026 in response to the Office Action of 10/01/2025 are acknowledged and have been entered.
Claims 67, 73, 75-105, 107-112, and 114-115 are currently pending.
Claims 67, 73, 75-77, 79, 80, 83, 89-94, 97-105, 107-11 and 114-115 have been amended by Applicant.
Claims 67, 73, 75-105, 107-112, and 114-115 are under examination in the instant Office Action.
The Examiner has rejoined the PDL1 antibody with VH as set forth in SEQ ID NO. 16 and VL as set forth in SEQ ID NO. 59 (claim 73), which comprises the VHCDR1, 2, 3 of SEQ ID NOs: 10, 12, 14 respectively and the VLCDR1, 2, 3 of SEQ ID NOs: 26, 35, and 37 respectively. The Examiner has also rejoined TIM3, HEVM and BTLA as the antigen on an immune cell (claim 76), as well as rejoined 4-1BB, ICOS or OX40 costimulatory domain (claim 99).
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
This Office Action contains new rejections.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The U.S. effective filing date of all claims under examination is set at 12/02/2019 based on the provisional application 62/942,455 (filed 12/02/2019).
Objections - Withdrawn
Applicant has amended the specification and so the specification objections have been withdrawn.
Applicant has canceled claims 65 and 66, and amended claims 67, 75-77, 83, 91, 94 97, 101, 104, 105 and 109. As such, the claim objections have been withdrawn.
Claim Rejections Withdrawn
The rejection of claims 65-67, 73, 75-105, 107-112, and 114-115 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AlA), second paragraph has been withdrawn.
The written description rejection of claims 65, 66, 67, 73-76, 78-105, 107-112, and 114-115 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph has been withdrawn.
The enablement rejection of claims 65-67, 73, 75-105, 107-112, and 114-115 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph has been withdrawn.
The enablement rejection of claims 79, 80, 89, 90, 102-105, 107-112, and 114-115 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph has been withdrawn.
The enablement rejection of claims 91-94 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph has been withdrawn.
The improper Markush Grouping rejection of claims 65-67, 73, 75-105, 107-112 has been withdrawn.
The rejection of claim 91 under 35 U.S.C. 102 as being clearly anticipated by Helliwell and Wilmink (US 20150112248 A1 Date Published 2015-04-23) has been withdrawn.
New Claim Objections
Claim 86 is objected to because of a typographical error. The claim should read “an siRNA” and not “a siRNA” because siRNA starts with a vowel sound.
New Claim Rejections
Claim Rejections - 35 USC § 112(b) - New
Claim 91 recites the phrase “the at least one antibody to a human subject” in lines 2-3. There is insufficient antecedent basis for " the at least one antibody” in the claim.
Claim Rejections - 35 USC § 102 - New
Claims 67, 73, 75-79, 81-87, 89, 90 and 92-94 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Marasco and Sui (WO2014055897A2 Date Published 2014-04-10).
Marasco and Sui teaches human monoclonal antibodies that bind to PD-L1 that inhibit binding of PD-L1 to its receptor PD1 and can be used to treat cancer and chronic viral infections (Abstract). They teach the binding of huPD-L1 antibodies with human PD-L1 (hPD-L1) expressing cells (Figure 2 and paragraph [0029]). They also teach a single chain antibody that binds to PD-L1 comprising a VH amino acid sequence comprising SEQ ID NO: 38 and a VL amino acid sequence comprising SEQ ID NO: 40 (paragraph [0011]). They further teach a cell comprising a vector that comprises nucleic acid sequences encoding the polypeptide of SEQ ID NOs: 38 and 40 (paragraphs [0022] and [0024]).
Alignment of VH SEQ IQ NO: 38 as taught by Marasco and Sui with instant VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences GYTLSSHG (instant SEQ ID NO: 10), ISAHNGHA (instant SEQ ID NO: 12), and ARVHAALYYGMDV (instant SEQ ID NO: 14) respectively, shows that instant VHCDR1, VHCDR2 and VHCDR3 are comprised within SEQ ID NO: 38 as taught by Marasco and Sui (see Alignment 1 below). Similarly, alignment of VL SEQ IQ NO: 40 as taught by Marasco and Sui with instant VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences NIGSKG (instant SEQ ID NO: 26), DDS (instant SEQ ID NO:35), and QVWDSSSDHWV (instant SEQ ID NO:37) respectively, shows that instant VLCDR1, VLCDR2 and VLCDR3 are comprised within SEQ ID NO: 40 as taught by Marasco and Sui (see Alignment 2 below).
Alignment 1: top sequence is instant SEQ ID NOs: 10, 12 and 14 and bottom sequence is SEQ ID NO: 38 as taught by Marasco and Sui
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Alignment 2: top sequence is instant SEQ ID NOs: 26, 35 and 37 and bottom sequence is SEQ ID NO: 40 as taught by Marasco and Sui
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Further, the alignment of instant heavy chain amino acid sequence according to instant SEQ ID NO: 16 with SEQ ID NO: 38 taught by Marasco and Sui, and the alignment of instant light chain amino acid sequence according to instant SEQ ID NO: 59 with SEQ ID NO: 40 taught by Marasco and Sui show that these sequences match exactly (see Alignments 3 and 4 below).
Alignment 3: top sequence is instant SEQ ID NO: 16 and bottom sequence is SEQ ID NO: 38 as taught by Marasco and Sui
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Alignment 4: top sequence is instant SEQ ID NO: 59 and bottom sequence is SEQ ID NO: 40 as taught by Marasco and Sui
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Therefore, Marasco and Sui teaches an antibody that binds to human PD-L1 protein wherein the antibody comprises a heavy chain variable region (VH) with VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences GYTLSSHG (instant SEQ ID NO: 10), ISAHNGHA (instant SEQ ID NO: 12), and ARVHAALYYGMDV (instant SEQ ID NO: 14) respectively, that is comprised within SEQ ID NO: 38 of Marasco and Sui that matches to instant SEQ ID NO: 16, and a light chain variable region with VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences NIGSKG (instant SEQ ID NO: 26), DDS (instant SEQ ID NO:35), and QVWDSSSDHWV (instant SEQ ID NO:37) respectively, that is comprised within SEQ ID NO: 40 of Marasco and Sui that matches to instant SEQ ID NO: 59.
Marasco and Sui teaches bispecific antibodies comprising two variable domains or scFv units that recognize PD-L1 and a second antigen which is a cell surface receptor that can be BTLA, HVEM or TIM3 (paragraphs [0013], [00161], [00174] to [00176]). They teach that these antibodies comprise CH3 domains or Fc regions that are favorable for constructing bispecific antibodies (paragraph [00166]).
Marasco and Sui teaches that monospecific or bispecific anti-PD-L1 antibodies can be incorporated into pharmaceutical compositions that comprise the antibodies or additional agents and a pharmaceutically acceptable carrier suitable for administration (paragraph [00136]). They teach a formulation can also contain, other than the anti-PD-L1 antibody fragments, more than one active compound as necessary for the particular indication being treated, alternatively, or in addition, the composition can comprise an agent that enhances function of the anti-PD-L1 antibody, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent (paragraph [00129]). They teach methods of treating cancer, comprising administering to a subject in need thereof a composition comprising anti-PD-L1 antibodies and/or bispecific anti-PD-L1 antibodies (paragraph [0019]). They also teach that the cancer is a cancer in which PD-L1 is overexpressed or the cancer is a cancer that induces T cell exhaustion through the PD-i/PD-L1 pathway (paragraphs [0004] and [0019]). As such, according to the claim interpretation presented in the First Office Action, these types of cancers read on “Checkpoint Blockade Cancers”.
Therefore, Marasco and Sui anticipates instant claims 67, 73, 75-87, 89, 90 and 92-94 and are rejected here.
Claim Rejections - 35 USC § 103 (first)- New
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 67, 73, 75-90, 92-94 and 114-115 are rejected under 35 U.S.C. 103 as being unpatentable over Marasco and Sui (WO2014055897A2 Date Published 2014-04-10) as applied to claims 67, 73, 75-79, 81-87, 89, 90 and 92-94 above, and further in view of Marasco and Sui (WO2014055897A2 Date Published 2014-04-10).
The teachings of Marasco and Sui are described above in the 102 rejection above.
Marasco and Sui does not specifically teach an isolated nucleic acid encoding a bispecific antibody comprising a first antigen-binding fragment and a second antigen binding fragment, wherein the first antigen-binding fragment comprises an antigen-binding fragment of instant claim 67, and wherein the second antigen-binding fragment has specificity to an antigen on an immune cell; or an isolated vector comprising the said isolated nucleic acid; or an isolated cell comprising the said isolated vector.
However, because Marasco and Sui also teaches bispecific antibodies comprising the anti-PD-L1 antibody and a second antigen binding domain which can bind to TIM3, HEVM or BTLA, one of ordinary skill in the art would have been motivated with an expectation of success to generate such bispecific antibodies by expressing an isolated expression vector comprising nucleic acid encoding a bispecific antibody comprising a first antigen-binding fragment that comprises a human PD-L1 binding fragment (according to instant claim 67) and a second antigen-binding fragment that binds to an immune cell antigen that is TIM3, HEVM or BTLA in a host cell by employing standard recombinant DNA techniques similar to those disclosed at Example 4 of Marasco and Sui. The reasons for generating said isolated nucleic acids encoding said bispecific antibodies, or for generating said vectors comprising said isolated nucleic acids encoding said bispecific antibodies, would be to facilitate in vivo production of said bispecific antibodies in host cells such that these therapeutic bispecific antibodies can be produced in large enough quantities for administering to a human in need for the treatment of cancer.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103 (second)- New
Claims 67, 73, 75-94 and 114-115 are rejected under 35 U.S.C. 103(a) as being unpatentable over Marasco and Sui (WO2014055897A2 Date Published 2014-04-10) as applied to claims 67, 73, 75-90, 92-94 and 114-115 above, and further in view of Yoo et al. (US 20190218297 A1 Date Published 2019-07-18).
The teachings of Marasco and Sui are described above in the 102 and first 103 rejections above.
While Marasco and Sui teaches that the antibodies of Marasco and Sui are to be administered intravenously, intradermally, subcutaneously, and/or injected (see page 36), Marasco and Sui does not specifically teach a kit comprising: the antibody according to instant claim 67; as well as a syringe, needle, or applicator for administration of the antibody to a human subject; and instructions for use.
However, these deficiencies are made up in the teachings of Yoo et al.
Yoo et al. teaches a therapeutic method of cancer treatment which comprises administering an antibody that binds specifically to glycosylated PD-L1 to a subject in need (Abstract). They teach anti-glycPD-L1 antibodies that bind to human PD-L1 and the subject is a human patient (paragraph [0105]). They also teach a kit containing therapeutic agents and/or other therapeutic and delivery agents for administering a therapy involving the combinations of two or more different anti-glycPD-L1 antibodies (paragraph [0210]). They further teach the kit may comprise a composition comprising the combination of two or more anti-glycosylated PD-L1 antibodies for administration, as well as reagents to prepare, formulate, and/or administer the combination of two or more anti-glycPD-L1 antibodies and a syringe, and may further include an instruction sheet that outlines the procedural steps of the methods (paragraphs [0210] and [0211]).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of preparing a kit comprising anti-glycPD-L1 antibodies, a syringe for administration of the antibody to a human subject and instructions for use as taught by Yoo et al. and substituting the anti-glycPD-L1 antibody of Yoo et al. with the anti-PD-L1 antibody comprising the amino acid sequence of SEQ ID NOs: 38 and 40 as taught by Marasco and Sui because a kit comprising said components enable convenient and directed administration of antibody therapeutics, as envisioned by Marasco and Sui, thereby enhancing treatment safety and compliance. This is an example of (B) Simple substitution of one known element for another to obtain predictable results. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103 (third)- New
Claims 67, 73, 75-90, 92-104, 107-112 and 114-115 are rejected under 35 U.S.C. 103(a) as being unpatentable over Marasco and Sui (WO2014055897A2 Date Published 2014-04-10) as applied to claims 67, 73, 75-90, 92-94 and 114-115 further in view of Novina (WO2017143076A1 Date Published 2017-08-24).
The teachings of Marasco and Sui are described above in the 102 rejection and the first 103 rejection above.
Marasco and Sui does not specifically teach a chimeric antigen receptor (CAR) comprising an intracellular signaling domain, a transmembrane domain and an extracellular domain, wherein the extracellular domain is an isolated monoclonal antibody or antigen-binding fragment thereof that binds to human Programmed death-ligand 1 (PD-L1) protein, wherein the monoclonal antibody or fragment thereof comprises an antibody according to instant claim 67. Marasco and Sui also does not specifically teach the CAR having the limitations as recited in instant claims 96-104 and 107-112.
However, these deficiencies are made up in the teachings of Novina.
Novina teaches chimeric antigen receptors (CARs), cells expressing same and methods of using same for treatment of various disorders (Abstract). They teach a CAR comprising an intracellular signaling domain, a transmembrane domain and an extracellular domain wherein the extracellular domain can include the variable region of a T-cell receptor specific for a tumor-associated antigen or for a self-antigen (paragraphs [0007] and [0008]). They also teach that the transmembrane domain further comprises a stalk region positioned between the extracellular domain and the transmembrane domain, and that the transmembrane domain comprises CD28 (paragraph [0009]). They further teach that the CAR further includes one or more additional costimulatory molecules positioned between the transmembrane domain and the intracellular signaling domain, wherein the costimulatory molecules can be CD28, 4-1BB, ICOS, or OX40 (paragraph [00010]). They also further teach the intracellular signaling domain comprises a CD3 zeta chain (paragraph [00011]).
Novina teaches a nucleic acid encoding the CAR, vectors comprising said nucleic acid and cells containing said vector (paragraph [00012]). They also teach a genetically engineered cell which expresses and bears on the cell surface membrane the said CAR, wherein said cell is a T cell such as a CD4+ T-cell and/or CD8+ T-cell, a T regulatory cell (Treg) or a T follicular regulatory cell (TFR) (paragraph [00013]). They further teach that a successful cancer immunotherapy using CAR T cells to treat B cell leukemias and lymphomas comprises a single chain antibody specific for CD 19 that is fused to CD28 (T cell co-stimulatory protein) and to CD3zeta (paragraph [00034]).
Novina also teaches Armed CARTs which are CARTs that are modified to secrete one or more polypeptides such as an antibody or cytokine (paragraph [00066]). They teach that Armed CARTs can be constructed by including a nucleic acid encoding the polypeptide of interest after the intracellular signaling domain (paragraph [00068]).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of generating a CAR comprising an intracellular signaling domain, a transmembrane domain and an extracellular domain, or an isolated nucleic acid encoding said CAR, or an isolated vector comprising said nucleic acid, or an isolated cell comprising said vector, or an isolated genetically engineered cell which expresses on the cell surface membrane said CAR as taught by Novina and substituting the extracellular domain of the CAR as taught by Novina with the anti-PD-L1 antibody as taught by Marasco and Sui because Novina teaches that T cells expressing CARs that can bind specifically to tumor antigens have been used successfully to treat cancers (paragraph [00034]), Marasco and Sui teaches that PD-L1 is a tumor antigen by disclosing that many cancers overexpress PD-L1 and that upregulation of PD-L1 is associated with high risk prognostic factors (paragraph [00123]), and further Marasco and Sui also teaches that a huPD-L1 antibody is able to block PD-1/PD-L1 binding and is capable of inducing cell death (paragraphs [0045] and [0167] to [0169]). In addition, Novina teaches that Armed CARTs have the advantage of simultaneously secreting a polypeptide at the targeted tumor site for enhanced therapeutic effects (paragraph [00067]). This is an example of (B) Simple substitution of one known element for another to obtain predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103 (fourth)- New
Claims 67, 73, 75-90, 92-105, 107-112 and 114-115 are rejected under 35 U.S.C. 103(a) as being unpatentable over Marasco and Sui (WO2014055897A2 Date Published 2014-04-10) and Novina (WO2017143076A1 Date Published 2017-08-24) as applied to claims 67, 73, 75-90, 92-104, 107-112 and 114-115 further in view of Rafiq et al. (Nat Biotechnol. 2018 Oct;36(9):847-856).
The teachings of Marasco and Sui and Novina are described above in the third 103 rejection above.
Marasco and Sui and Novina do not specifically teach an isolated nucleic acid encoding the CAR according to instant claim 95, wherein the isolated nucleic acid further comprises a nucleic acid encoding a polypeptide positioned after the intracellular signaling domain wherein the polypide is an antibody that is a scFv.
However, these deficiencies are made up in the teachings of Rafiq et al.
Rafiq et al. teaches a CAR construct that has been engineered to co-express factors that boost CAR-T cell function in the tumor microenvironment (Abstract). They teach modified CAR-T cells that secrete PD-1-blocking single-chain variable fragments (scFv) wherein the scFv-secreting CAR-T cells work in both a paracrine and autocrine manner to improve the anti-tumor activity of CAR-T cells and bystander tumor-specific T cells in clinically relevant syngeneic and xenogeneic mouse models of PD-L1+ hematologic and solid tumors (Abstract). They also teach that the nucleotide sequence encoding the PD-1 blocking scFv, RMP1-14, is positioned after the CD3 zeta intracellular signaling domain (Figure 1a).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of generating an isolated nucleic acid encoding a CAR as taught by Novina, that comprises an anti-PD-L1 antigen-binding fragment as taught by Marasco and Sui, and further comprises a nucleic acid encoding a secretable antibody scFv fragment that is positioned after the intracellular signaling domain as taught by Rafiq et al. because Rafiq et al. teaches that co-expression of CAR and a secretable scFv in a T cell is feasible and that this combination protects the proliferative and lytic capacity of T cells as well as provide enhanced anti-tumor functions in vivo (Figures 1, 4 and 5). This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Conclusion
No claims are allowed.
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/YIE-CHIA LEE (TONYA)/Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642