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 .
DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01/16/2026 has been entered.
Applicant's response filed on 01/16/2026 has been received and entered into the case.
Claim Status
Claims 1-4, 7-8, 10-12, 14, 16, 22, 24, 37, 40-41 and 44-45 are pending.
Claims 7, 16, 40 and 44-45 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/20/2024.
Claims 1-4, 8, 10-12, 14, 22, 24, 37 and 41 are considered on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/16/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. The corresponding signed and initialed PTO form 1449 has been mailed with this action.
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.
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.
Rejections over an anti-carbonic anhydrase IX (CAIX) CAR
Claims 1-4, 8, 10-11, 14, 22, 37 and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Suarez et al., (Oncotarget. 2016; 7(23): 34341-34355. Prior art of record) in view of Zhang et al., (Cell Discovery. 2017; 3: 17004, p. 1-12).
With respect to claim 1, Suarez teaches a combination immunotherapy comprising CAR-T cells engineered to secrete human anti-PD-L1 antibodies at the tumor site (abstract, p. 34342, right col, see Fig 1). Suarez teaches an anti-CAIX CAR comprises an anti-CAIX scFv and CD28/CD3ζ signaling domain (see e.g., Fig 1B attached below). Thus, Suarez teaches claim 1 preamble and limitation (i): an engineered cell comprising (i) a nucleotide sequence encoding a CAR (i.e., an anti-CAIX CAR T cell) comprising an extracellular target-binding moiety (i.e., an anti-CAIX scFv) and an intracellular signaling domain (i.e., a CD28/CD3ζ signaling domain).
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In regard to limitation (ii), as stated supra, Suarez teaches the CAR T cell is engineered to secrete human anti-PD-L1 antibodies (see e.g., p. 34342, right col and Fig 1B attached above), thus teaches the engineered cell comprises (ii) a nucleotide sequence encoding an antibody wherein the engineered cell secretes the antibody.
However, Suarez is silent on the antibody being a heavy-chain antibody (VHH).
Zhang teaches a secretory anti-PD-L1 nanobody (named KN035, which is a VHH antibody) (e.g., abstract and p. 9, left col, section “Generation of camel nanobodies against PD-L1”). Zhang teaches KN035 can strongly induce T-cell responses and inhibit tumor growth comparable to that of durvalumab, an antibody developed by AstraZeneca showing promising readouts in multiple phase III clinical trials, and teaches the anti-PD-L1 VHH has smaller size and favorable physico-chemical properties that offer great potential in immuno-oncology applications and for combination therapy (e.g., p. 2, para 1 and abstract).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the engineered T cell comprising an anti-CAIX CAR and an anti-PD-L1 scFv antibody for a combination immunotherapy disclosed by Suarez, by substituting the nucleotide sequence encoding the anti-PD-L1 scFv antibody with a nucleotide sequence encoding the anti-PD-L1 VHH (KN035) as suggested by Zhang with a reasonable expectation of success. Since Suarez teaches a combination immunotherapy comprising CAR-T cells engineered to secrete human anti-PD-L1 antibodies at the tumor site (abstract, p. 34342, right col), and since Zhang teaches KN035 can strongly induce T-cell responses and inhibit tumor growth comparable to that of an antibody confirmed in multiple phase III clinical trials and the anti-PD-L1 VHH has smaller size and favorable physico-chemical properties that offer great potential in immuno-oncology applications and for combination therapy (e.g., p. 2, para 1 and abstract), one of ordinary skill in the art would have had a reason to substitute with the anti-PD-L1 VHH KN035 as suggested by Zhang in engineering the CAR T cell of Suarez in order to take advantage of its strong induction of T-cell responses and inhibition of tumor growth and its smaller size and favorable physico-chemical properties that offer great potential in combination immunotherapy as suggested by Zhang.
With respect to claim 2 directed to (i) being operably linked to a first promoter, as shown in the attached Fig 1B, the nucleotide sequence encoding the CAR is operably linked to an eIFa promoter (see above).
With respect to claim 3 directed to (i) being operably linked at the 5’ end to a nucleotide sequence encoding a signal sequence, as shown in the attached Fig 1B above, the nucleotide sequence encoding the CAR is operably linked at the 5’ end to a signal sequence (see above, “signal” between the eIFa promoter and the scFv).
With respect to claim 4 directed to (i) and (ii) being linked via an IRES, Suarez teaches the nucleotide sequences encoding the CAR (i) and the antibody (ii) are located in a single multicistronic vector linked via an IRES (see Fig 1B attached for “IRES”).
With respect to claim 8 directed to (i) and (ii) being located on the same vector, as stated supra, Suarez teaches the nucleotide sequences encoding the CAR (i) and the antibody (ii) are located in a single multicistronic vector (see Fig 1B attached).
With respect to claim 10 directed to the extracellular target-binding moiety of the CAR being an antibody and claim 11 directed to the antibody being a scFv, as stated supra, Suarez teaches the anti-CAIX CAR comprises an anti-CAIX scFv antibody (see Fig 1B attached).
With respect to claim 14 directed to the extracellular target-binding moiety binding a tumor-associated antigen, as stated supra, Suarez teaches the CAR binds CAIX, which is overexpressed in solid tumors and is the most well-characterized tumor-associated antigen overexpressed in ccRCC (p. 34342, left col, last para).
With respect to claim 22 directed to the VHH binding an immune checkpoint protein, as stated supra, Zhang teaches the anti-PD-L1 nanobody VHH KN035 binds an immune checkpoint protein PD-L1 (see e.g., title and abstract).
With respect to claim 37 directed to the cell being an immune cell, as stated supra, Suarez teaches an engineered CAR T cell secreting an anti-PD-L1 antibody (e.g., abstract), thus teaches an immune cell, i.e., a T cell.
With respect to claim 41 directed to a composition comprising the engineered cell, Suarez teaches an in vivo mouse tumor model into which the engineered CAR T cells are injected intravenously in the tail vein (e.g., p. 34352, last para). Thus, Suarez teaches a composition comprising the engineered cell.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Claims 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Suarez et al., (Oncotarget. 2016; 7(23): 34341-34355. Prior art of record) in view of Zhang et al., (Cell Discovery. 2017; 3: 17004, p. 1-12), as applied to claims 1 and 10 above, and further in view of van Brussel et al., (Mol Imaging Biol. 2016;18:535-544) and Jamnani et al., (Biochimica et Biophysica Acta. 2014; 1840: 378-386).
Claims 11 and 12 are directed to the extracellular target-binding moiety of the CAR being a single domain antibody.
However, Suarez uses an anti-CAIX scFv as the extracellular target-binding moiety of the CAR, but is silent on an anti-CAIX single domain antibody in the CAR.
van Brussel teaches generation of CAIX-specific nanobodies from a new second-generation family-specific library (i.e., anti-CAIX single domain antibodies, see e.g., abstract). van Brussel teaches nanobodies possess several advantageous properties such as smaller sizes, high-affinity, more stable than other antibody-fragments and known to be non-immunogenic (e.g., p. 536, left col, last para to right col, para 1). van Brussel teaches the CAIX-specific nanobodies, such as clones C5, B9 and E4, have improved affinity to CAIX-overexpressing tumor cells (see e.g., p. 538, left col, section “Nanobody Characterization” and Fig 2).
In regard to using single domain antibody in a CAR, Jamnani teaches genetically engineering T cells armed with a CAR comprising the anti-HER2 VHH as targeting moiety (e.g., abstract, it is noted that VHH is a single domain antibody). Jamnani teaches a scFv derived from a murine monoclonal antibody causes the human anti-mouse antibody responses and potentially limit the life span of engineered CAR T cells, and the humanization of mouse antibodies by CDR grafting is labor intensive and does not fully abrogate immunogenicity, and thus uses camelid single-domain antibody as a binding domain of CAR instead of the scFv as “one fascinating strategy” as they are small, highly homologous to human VH, and easily generated (e.g., p. 379, left col, para 2). Jamnani teaches the engineered T cells showed higher proliferation, cytokine secretion and cytotoxicity and teaches the combination of superior targeting ability of VHHs with the third generation CAR can substantially improve the function of engineered T cells (e.g., abstract).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the engineered CAR T cell comprising an anti-CAIX scFv as the extracellular target-binding moiety of the CAR suggested by Suarez in view of Zhang, by substituting the anti-CAIX scFv antibody with an anti-CAIX single domain antibody as the target-binding moiety of the CAR as suggested by van Brussel and Jamnani with a reasonable expectation of success. Since van Brussel reduces to practice an anti-CAIX single domain antibody with high affinity to CAIX-overexpressing tumor cells (above), and since both van Brussel and Jamnani teach single domain antibodies are small, highly homologous to human VH, more stable, non-immunogenic and have high-affinity, and Jamnani teaches the VHH-directed CAR T cells have superior targeting ability and improved function (see above), one of ordinary skill in the art would have had a reason to substitute the scFv with a single domain antibody as the targeting moiety in the CAR as suggested by van Brussel and Jamnani in order to take the advantages of the single domain antibody such as high-affinity, being more stable and non-immunogenic.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Rejections over an anti-PD-L1 CAR
Claims 1-4, 8, 14, 22, 24, 37 and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Brogdon et al., (WO 2017/112741 A1. Prior art of record) in view of Ingram et al., (PNAS. 2017; 114(38): 10184-10189. Prior art of record) and Suarez et al., (Oncotarget. 2016; 7(23): 34341-34355. Prior art of record).
With respect to claim 1, Brogdon teaches a CAR-engineered immune cell comprising an anti-mesothelin CAR and co-expressing an agent that enhances CAR activity (p. 91). Brogdon teaches in one embodiment, the agent comprises the extracellular domain (ECD) of an inhibitory molecule, e.g., Programmed Death 1 (PD1), can be fused to a transmembrane domain and intracellular signaling domains such as 41BB and CD3 zeta (also referred to herein as a PD1 CAR) (p. 92, para 2. It is noted that this PD1 CAR corresponds to the CAR in claim 1 (i)), thus teaches a chimeric antigen receptor (CAR) comprising an extracellular target-binding moiety (i.e., the extracellular domain of PD1) and an intracellular signaling domain (i.e., 41BB and CD3 zeta). Brogdon teaches a nucleic acid sequence encoding the PD1 CAR, thus teaches claim 1 (i). Brogdon teaches PD-L1 is a ligand for PD1 (p. 92, para 1), thus teaches the extracellular target-binding moiety of the CAR (i.e., the extracellular domain of PD1) binds PD-L1 in claim 24 (a).
However, Brogdon is silent on the engineered cell comprising a nucleotide sequence encoding a secretory VHH that binds CD47 in claim 1 (ii), claim 4, claim 8, claim 22 and claim 24 (a).
Nevertheless, Brogdon teaches a method of treating cancer, including melanoma, by administering the T cells expressing a mesothelin CAR and the PD1 CAR and co-administering an anti-PD-L1 antibody (abstract, e.g., p. 189, para 2).
Regarding a secretory VHH that binds CD47, Ingram teaches a secretory anti-CD47 VHH antibody (abstract). Ingram teaches CD47 is an innate checkpoint receptor broadly expressed on malignant tissues that delivers an inhibitory signal, and an anti-CD47 nanobody (named A4, which is a VHH antibody) synergizes with anti-PD-L1 antibody therapy in a melanoma model (abstract and p. 10184, para 1). Ingram teaches a nucleotide sequence of the anti-CD47 nanobody is transduced into a melanoma cell line to locally secrete the A4 nanobody that effectively blocks CD47 both on tumor-infiltrating leukocytes (TILs) and tumor cells in the tumor microenvironment and enhances anti-melanoma immune therapy (abstract and p. 10186, see Figs 3-4). Thus, Ingram teaches a nucleotide sequence encoding a secretory VHH that binds CD47 in claims 1(ii), 22 and 24(a).
Regarding an engineered immune cell comprising nucleotide sequences encoding a CAR and a secretory antibody, Suarez teaches a single bicistronic lentiviral vector to develop a combination immunotherapy that consists of CAR-T cells engineered to secrete human anti-PD-L1 antibodies at the tumor site (abstract, p. 34342, right col, see Fig 1). Suarez teaches the local antibody delivery led to marked immune checkpoint blockade and enhanced anti-tumor effect (abstract, p. 34345-34346, see Figs 4-5). Suarez teaches the nucleotide sequences encoding the CAR and the antibody are located in the same vector and are separated by an IRES (see Fig 1B), related to claims 1 (ii), 4 and 8.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the engineered immune cell comprising a nucleotide sequence encoding a PD1 CAR disclosed by Brogdon, by combining a nucleotide sequence encoding a secretory VHH that binds CD47 in the same expression vector of the PD1 CAR separated by an IRES as taught by Ingram and Suarez with a reasonable expectation of success. Since Brogdon teaches the CAR-T cells are co-administered with an anti-PD-L1 antibody to treat melanoma (abstract, see p. 189, para 2), since Ingram teaches the anti-CD47 VHH synergizes with anti-PD-L1 antibody therapy in a melanoma model and local secretion of the anti-CD47 VHH in the tumor microenvironment enhances anti-melanoma immune therapy (abstract), and since Suarez reduces to practice engineering T cells with a single vector comprising a CAR and a secretory antibody can locally secrete the antibody at the tumor site resulting in enhanced anti-tumor effect (abstract, p. 34345-34346, see Figs 4-5), one of ordinary skill in the art would have had a reason to combine a nucleotide sequence encoding an anti-CD47 VHH in the expression vector of the CAR suggested by Ingram and Suarez to arm the PD1 CAR T cells of Brogdon with secretory anti-CD47 VHH antibody in order to obtain local delivery of the anti-CD47 VHH to the tumor microenvironment to enhance anti-melanoma immune therapy (Ingram, abstract).
In regard to a reasonable expectation of success, it would be predictably obvious to combine a secretory anti-CD47 VHH when engineering the PD1 CAR T cell of Brogdon. In re O' Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988) (citations omitted) (The court held the claimed method would have been obvious over the prior art relied upon because one reference contained a detailed enabling methodology, a suggestion to modify the prior art to produce the claimed invention, and evidence suggesting the modification would be successful.). Therefore, one of ordinary skill in the art could have pursued the known potential option of combining a secretory anti-CD47 VHH in the PD1 CAR T cell with a reasonable expectation of success. This reasonable expectation of success is supported by: (1) the reference of Brogdon contains a detailed enabling methodology of engineering T cells with an expression vector comprising the PD1 CAR, that could easily be modified to add other elements, e.g., a sequence encoding a secretory anti-CD47 VHH, in the expression vector, (2) Ingram provides a suggestion to locally secret the anti-CD47 VHH to the tumor microenvironment to enhance anti-melanoma immune therapy, and (3) the success of combination immune therapy by a CAR T cell engineered to secret an anti-checkpoint antibody in the tumor microenvironment as taught by Suarez suggest modification of the engineered PD1 CAR T cell of Brogdon to include other elements in the expression vector (to wit, a secretory anti-CD47 VHH) would be successful.
With respect to claim 2 directed to the nucleotide sequence of (i) being operably linked to a first promoter, Brogdon teaches the expression of the CAR is achieved by operably linking a nucleic acid encoding the CAR polypeptide to a promoter and incorporating the construct into an expression vector (e.g., p. 99, para 2), thus teaches the nucleotide sequence of the PD1 CAR is operably linked to a first promoter.
With respect to claim 3 directed to the nucleotide sequence of (i) or (ii) being operably linked at the 5’ end to a nucleotide sequence encoding a signal sequence, Brogdon teaches a N-terminal (i.e., at the 5’ end) signal sequence in PD1 CAR (see p. 92, last para), and Ingram teaches a tPA signal peptide at the 5’ end of the VHH A4 (see Fig 3A diagram), thus teaches a 5’ signal sequence for (i) and (ii).
With respect to claim 14 directed to the extracellular target-binding moiety of the CAR binding a tumor-associated antigen, Brogdon teaches the extracellular target-binding moiety of the CAR (i.e., the extracellular domain of PD1) binds PD-L1 (p. 92, para 1), and teaches the combinatory therapy is more effective for a cancer that expresses, e.g., highly expresses, PD-L1 (p. 46, para 1). Thus, Brogdon teaches the PD1 CAR binds PD-L1, which is a tumor-associated antigen.
With respect to claim 37 directed to the cell being an immune cell, Brogdon teaches the cell is a T cell or an NK cell (p. 19, para 4), and Suarez teaches CAR-T cells secreting an antibody (abstract). Thus, Brogdon and Suarez teach the cell is an immune cell.
With respect to claim 41 directed to a composition comprising the engineered cell of claim 1, Brogdon teaches a pharmaceutical composition that comprises a CAR-expressing cell, e.g., a plurality of CAR-expressing cells, in combination with one or more pharmaceutically or physiologically acceptable carriers, diluents or excipients (p. 229, section “Pharmaceutical Compositions”).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments and prior art Wesolowski filed on 01/16/2026 are acknowledged.
Applicant firstly argues that the results of practicing the claimed invention would not have been predictable based on Brogdon, Ingram, and Suarez, because combining a CAR and a secretory VHH in a single cell would not have been predicable to be effective in treating cancer or in preventing T cell exhaustion and reducing antibody dosing. Particularly, because VHH antibodies and IgG antibodies are distinct (in that VHH has a longer CDR3 taught by Wesolowski), the effects of IgG antibodies do not predict that VHH antibodies will have the same effects (Remarks, p. 7-8).
Applicant’s arguments have been fully considered but they are not persuasive.
As stated supra, one of ordinary skill in the art would have had a reason to combine a secretory VHH in the CAR T cell with a reasonable expectation of success because: (1) the reference of Brogdon contains a detailed enabling methodology of engineering T cells with an expression vector comprising the PD1 CAR, that could easily be modified to add other elements, e.g., a sequence encoding a secretory anti-CD47 VHH, in the expression vector, (2) Ingram provides a suggestion to locally secret the anti-CD47 VHH to the tumor microenvironment to enhance anti-melanoma immune therapy, and (3) the success of combination immune therapy by a CAR T cell engineered to secret an anti-checkpoint antibody in the tumor microenvironment as taught by Suarez suggest modification of the engineered PD1 CAR T cell of Brogdon to include other elements in the expression vector (to wit, a secretory anti-CD47 VHH) would be successful.
In regard to predictably treating cancer, preventing T cell exhaustion and reducing antibody dosing, as stated supra, Ingram teaches locally secreting the anti-CD47 VHH to the tumor microenvironment to enhance anti-melanoma immune therapy (i.e., being predicable in treating cancer). Ingram teaches multiple injections of an anti-CD47 nanobody fail to achieve complete blockade of CD47 in the tumor microenvironment (i.e., systemic delivery, see p. 10185), while local secretion of A4 induces near-complete blockade of CD47 in the tumor microenvironment (i.e., local secretion, see p. 10186), thus suggests that local secretion of CD47 single domain antibody in the tumor microenvironment would have been predictable in reducing antibody dosing (as compared to multiple injections) with improved effects. Suarez teaches local secretion of anti-PD-L1 antibodies in the tumor microenvironment by the CAR-T cell prevents T cell exhaustion (e.g., abstract), thus suggests that local secretion of an anti-CD47 antibody in the tumor microenvironment would have been predictable in preventing T cell exhaustion (it is noted that both CD47 and PD-L1 are immune checkpoint proteins that lead to T cell exhaustion, as disclosed by the instant specification “CAR T cells that secrete VHHs that target checkpoint molecules are of interest. They would enhance CAR T cell persistence and activity in the immunosuppressive tumor microenvironment”, see p. 60).
In regard to the argument that VHH antibodies and IgG antibodies are distinct (in that VHH has a longer CDR3 taught by Wesolowski), thus the effects of IgG antibodies do not predict that VHH antibodies will have the same effects (Remarks, p. 7-8), although Wesolowski teaches VHH antibodies and IgG antibodies are distinct in CDR3 region, Wesolowski specifically teaches that “this long fingerlike extensions can extend into cavities on antigens, e.g., the active site crevice of enzymes” (thus being advantageous), and “Other advantageous features of nanobodies include their small size, high solubility, thermal stability, refolding capacity, and good tissue penetration in vivo” (e.g., abstract). Wesolowski further teaches that while the conventional antibodies are used to treat diseases such as cancers, “the very high cost of conventional antibodies is already becoming a major burden for the health care budgets in many countries”, and “owing to their smaller size and ease of production, sdAbs present an interesting alternative to conventional antibodies for immune therapy.” (p. 160, last section “Single domain antibodies in immunity” to p. 161, right col, para 1). In summary, the cited prior art Wesolowski clearly supports that VHH antibodies (the single domain antibodies) present an alternative to conventional IgG antibodies, such that the VHH antibodies would have had the same effects as, or even improved effects than, the conventional antibodies, thus supports a reasonable expectation of success.
Applicant further argues that the present application is based on the unexpected results that the claimed engineered cells: (1) reduce antibody dosing by secreting VHH antibodies, (2) prevent T cell exhaustion, and (3) increase tumor cell killing with decreased toxicity in vivo (Remarks, p. 6-7).
Applicant’s arguments have been fully considered but they are not persuasive.
As stated supra, Ingram and Suarez suggest that the engineered CAR T cell armed with secretory anti-CD47 VHH would have been predictable in reducing antibody dosing by locally secreting VHH antibodies, preventing T cell exhaustion in tumor microenvironment, and increasing tumor cell killing with decreased systemic toxicity in vivo. Thus, the engineered cell comprising a CAR and a secretory VHH suggested by prior art would have been expected to have the claimed results.
Furthermore, MPEP § 2145 states that a showing of surprising results must be based on evidence, not argument or speculation. In re Mayne, 104 F.3d 1339, 1343-44, 41 USPQ2d 1451, 1455-56 (Fed. Cir. 1997) (conclusory statements that claimed compound possesses unusually low immune response or unexpected biological activity that is unsupported by comparative data held insufficient to overcome prima facie case of obviousness). In the instant case, the percentage of B16 killing shown in Figure 9 does not seem to be different between CAR-T cells (“A12”) and CAR-T cells secreting VHH (“A12 P2A A4”). Thus, Applicant’s argument that the engineered cell of the present claims that secretes VHH locally is more effective in vitro, is not supported by Applicant’s own side-by-side comparative data shown in Figure 9.
Finally, MPEP 716.02(d) states that unexpected results must be commensurate in scope with the claimed invention. In the instant case, the purported unexpected results presented by the Applicant were studies performed using a specific type of immune cell (i.e., T cell) expressing a specific CAR and secreting a specific VHH, i.e., an “A12” anti-PD-L1 VHH CAR T cell that secretes an “A4” anti-CD47 VHH antibody (see Figs 9 and 11, Remarks, p. 7) or secretes an “A4Fc” VHH (see Figs 18-19 and 21, Remarks, p. 7, para 2), or a “B2” anti-EIIIB CAR T cell that secretes an “A12” andti-PD-L1 VHH (Figs 29-31) or an “H11 Fc” anti-CTLA4 VHH (Fig 32, Remarks, p. 7). This is not commensurate in scope with the claimed genus of engineered cell (any cell) comprising a CAR (any CAR) and a secretory VHH (any VHH).
Maintained Double Patenting Rejections
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-4, 8, 10-12, 14, 22, 24, 37 and 41 stand rejected on the ground of nonstatutory double patenting as being unpatentable over claims of US Patent No. 12,454,576 (‘576) (from allowed Application No. 18/175,786) in view of Ingram et al., (PNAS. 2017; 114(38): 10184-10189. Prior art of record) and Suarez et al., (Oncotarget. 2016; 7(23): 34341-34355. Prior art of record). Although the claims at issue are not identical, they are not patentably distinct from each other.
Patent claims recite a CAR-T cell having the CAR construct of copending claim 49 comprising a nucleic acid encoding a CAR having an ectodomain comprised of a nanobody (i.e., a single domain antibody) which is specific for and binds directly to a diseased stated ECM epitope, the diseased state ECM epitope being an epitope in EIIIB domain of fibronectin. Thus, patent claims recite an engineered immune cell comprising a nucleotide sequence encoding a CAR comprising an extracellular target-binding moiety binding EIIIB fibronectin, related to instant claims 1(i), 10, 11, 12, 14, 24(b), 37 and 41.
However, copending claims are silent on the engineered cell comprising a nucleotide sequence encoding a secretory VHH that binds CD47 in claim 1(ii), 2-4, 8, 22 and 24(b).
Regarding a secretory VHH that binds CD47, Ingram teaches a secretory anti-CD47 VHH antibody (abstract). Ingram teaches CD47 is an innate checkpoint receptor broadly expressed on malignant tissues that delivers an inhibitory signal and an anti-CD47 nanobody (named A4, which is a VHH antibody) synergizes with immunotherapy in a melanoma model (abstract and p. 10184, para 1). Ingram teaches a nucleotide sequence of the anti-CD47 nanobody is transduced into a melanoma cell line to locally secrete the A4 nanobody that effectively blocks CD47 in the tumor microenvironment and enhances anti-melanoma immune therapy (abstract and p. 10186, see Figs 3-4). Ingram teaches the VHH sequence is operably linked at the 5’ end to a signal sequence (see Fig 3A diagram). Thus, Ingram teaches a nucleotide sequence encoding a secretory VHH that binds CD47 in claims 1(ii), 3, 22 and 24(b).
Regarding an engineered immune cell comprising a nucleotide sequence encoding a CAR and a secretory antibody, Suarez teaches a single bicistronic lentiviral vector to develop a combination immunotherapy that consists of CAR-T cells engineered to secrete human anti-PD-L1 antibodies at the tumor site (abstract, p. 34342, right col, see Fig 1). Suarez teaches the local antibody delivery led to marked immune checkpoint blockade and enhanced anti-tumor effect (abstract, p. 34345-34346, see Figs 4-5). Suarez teaches the nucleotide sequences encoding the CAR and the antibody are located in the same vector and are separated by an IRES, the CAR is operably linked to a promoter, the CAR is operably linked at the 5’ end to a signal sequence (see Fig 1B), related to claims 1 (ii), 2, 3, 4 and 8.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the engineered immune cell comprising a nucleotide sequence encoding a CAR binding EIIIB fibronectin recited in the patent claims, by combining a nucleotide sequence encoding a secretory VHH that binds CD47 in the same expression vector of the CAR separated by an IRES as taught by Ingram and Suarez with a reasonable expectation of success. Since patent claims recite the CAR-T cells bind to diseased state ECM epitope, since Ingram teaches the anti-CD47 VHH synergizes with immunotherapy in a melanoma model and local secretion of the anti-CD47 VHH in the tumor microenvironment enhances anti-melanoma immune therapy (abstract), and since Suarez teaches engineered T cells transduced with a single vector comprising a CAR and an antibody separated by an IRES can locally secrete antibodies at the tumor site resulting in enhanced anti-tumor effect (abstract, p. 34345-34346, see Figs 4-5), one of ordinary skill in the art would have had a reason to combine a nucleotide sequence encoding an anti-CD47 VHH in the expression vector of the CAR taught by Ingram and Suarez to arm the engineered CAR-T cell binding EIIIB fibronectin with a secretory anti-CD47 VHH in order to achieve local delivery of an anti-CD47 VHH to the tumor microenvironment to enhance anti-melanoma immune therapy (Ingram, abstract).
Since the instant application claims are obvious over cited patent claims, in view of Ingram and Suarez, said claims are not patentably distinct.
Response to Traversal:
Applicant’s arguments filed on 01/16/2026 are acknowledged and have been discussed above.
Conclusion
No claims are allowed.
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/JIANJIAN ZHU/Examiner, Art Unit 1631
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