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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 November 19, 2025 has been entered.
Application Status
The amended claims filed November 19, 2025 are acknowledged. Claims 49, 53-55, 57-64, and 66-70 are pending. Claims 49, 53-54, 57-60, 62-64, and 69-70 have been amended. Claims 57-58 and 66-67 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 49, 53-55, 59-64, and 68-70 are under examination herein.
Objection to Specification Withdrawn
The objection to the specification is withdrawn in view of Applicant's amendment to ¶ 0057.
Claim Rejections Withdrawn
The rejection of claims 53, 55, and 60 under 35 U.S.C. § 112(b) are withdrawn in view of Applicant’s amendments to claims 53 and 60.
The rejection of claims 53 and 55 under 35 U.S.C. § 112(d) are withdrawn in view of Applicant's amendments to claim 53.
OBJECTIONS AND REJECTIONS BASED ON RECONSIDERATION OF THE CLAIMS
Claim Objections
Claim 62 is objected to because the claim recites, at lines 7-8, “DNAM-1 encoded by a polynucleotide encoding comprising the nucleic acid sequence of SEQ ID NO: 23…”. It is suggested that the recitation of “encoding” (underlined herein) should be removed for clarity.
Claim 63 is objected to because the claim contains recitations of “transmembrane adaptor”, whereas earlier claims (e.g., claims 53 and 55) and the specification use the spelling “transmembrane adapter”.
Claim 70 is objected to because the claim recites a polynucleotide comprising “the nucleic acid sequence [singular] of …” in each list item. It is suggested that “nucleic acid sequence” should instead recite “nucleic acid sequences” in each of (i) through (v) since multiple sequences are comprised in the claimed polynucleotide.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 63 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. This is a new rejection necessitated by the amendments to the claims.
Claim 63 recites, in lines 7-8 and lines 11-12, that the CAR construct comprised in the CAR ML NK cell of claim 49 comprises “the transmembrane adaptor comprising DAP10”. There is insufficient antecedent basis for this limitation in the claim. Neither the claim, nor claim 49 from which it depends, earlier recites “a transmembrane adaptor” (or “a transmembrane adapter”) to which these limitations may refer.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 62 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. This is a new rejection.
Claim 62 recites that the at least one intracellular signaling domain of the CAR construct is selected from the closed group consisting of four members including CD137, DNAM-1, 2B4, and IL15RB. However, independent claim 49 earlier recites that the CAR construct comprises “at least one intracellular signaling domain selected from CD137, IL-15R, and 2B4” (a group with three members). The dependent claim fails to include all of the limitations of the claim from which it depends, because the selection of DNAM-1 (encoded by a polynucleotide … comprising the nucleic acid sequence of SEQ ID NO: 23) as the at least one intracellular signaling domain does not meet the limitations set forth in claim 49 stating that at least one intracellular signaling domain is selected from CD137, IL-15R, and 2B4.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 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.
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.
(1)
Claims 49, 53-55, 60, 62-63, and 68 are rejected under 35 U.S.C. 103 as being unpatentable over Campana (US 2013/0266551 A1; cited in IDS) in view of Fehniger (Trends in Immunology (2016) 37(12): 877-888; cited in PTO-892 mailed February 11, 2025). This is a maintained rejection that has been updated based on further consideration of the claims.
Campana teaches chimeric antigen receptors (CARs) expressed in natural killer (NK) cells (Abstract; ¶ 0003). Relevant to claims 49 and 63, Campana teaches a chimeric antigen receptor comprising an anti-CD19 scFv domain, a hinge region and transmembrane domain of CD8α, and a cytoplasmic (intracellular) domain comprising CD137 (4-1BB) and CD3ζ signaling domains, which may be expressed in an NK cell (¶ 0015, 0019). While not expressly disclosed by Campana, absent a showing otherwise, the CAR described by Campana would be capable of being expressed and functioning in a memory-like (ML) NK cell.
Regarding claims 53 and 55, the instant specification sets forth, “NK cells express a number of transmembrane (TM) adapters that signal activation, that are triggered via association with activating receptors. This provides an NK cell specific signal enhancement via engineering the TM domains from activating receptors, and thereby harness endogenous adapters. The TM adapter can be any endogenous TM adapter capable of signaling activation. For example, the TM adapter can be FceR1γ (ITAMx1), CD3ζ (ITAMx3), DAP12 (ITAMx1), or DAP10 (YxxM/YINM)” (page 19). See also Figure 4. The CAR construct taught by Campana, having an anti-CD19 scFv, a CD8α hinge and transmembrane region, and an intracellular signaling domain comprising CD137 and CD3ζ as similarly set forth in the instant claims, would, in view of Applicant's disclosure, form a complex with an endogenous transmembrane adapter such as those set forth in claims 53 and 55. Applicant is reminded that products of identical composition cannot have mutually exclusive properties. A chemical composition and its properties are inseparable. In re Spada 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). See MPEP § 2112.01.
Relevant to claim 60, Campana discloses a nucleotide sequence (SEQ ID NO: 13, which shares 100% identity to instant SEQ ID NO: 19) that encodes a CD8α transmembrane domain (¶ 0045; page 34).
Relevant to claim 62, Campana also discloses a nucleotide sequence (SEQ ID NO: 15, which shares 100% identity to instant SEQ ID NO: 22) that encodes a 4-1BB signaling domain (¶ 0048; page 34).
Campana further discloses a method of treating a mammal suffering from cancer, comprising introducing into the mammal an NK cell comprising a CAR that comprises an anti-CD19 scFv domain, a hinge region and a transmembrane domain of CD8α, and a cytoplasmic domain comprising 4-1BB and CD3ζ signaling domains (¶ 0026-0027). Campana further discloses that in aspects of the invention, NK cells from a patient having a cancer of B-cell origin are isolated, transduced with a polynucleotide encoding a CAR (“CD19-BB-ζ”), and readministered to the patient to target and kill tumor cells (¶ 0085), relevant to claim 68. The “CD19-BB-ζ” CAR comprises an anti-CD19 scFv, a CD8α hinge and transmembrane domain, and an intracellular domain comprising 4-1BB and CD3ζ (¶ 0054-0055; Figure 1).
However, Campana does not expressly teach a memory-like (ML) NK cell comprising a CAR construct, nor a method of administering such CAR-ML NK cells.
Fehniger reviews the properties of ML NK cells and how these cells may be harnessed for cancer immunotherapy (Abstract). Fehniger teaches that cytokine signaling is important for the differentiation, survival, homeostasis, and activation of NK cells (page 881). Per Fehniger, short-term cytokine activation with high-dose IL-12 and IL-18 in mouse NK cells and with combinations of IL-12, IL-15, and/or IL-18 in human NK cells was reported to give rise to a population of NK cells (termed “cytokine-induced memory-like NK cells”) having durable enhanced responses to re-stimulation (page 881). These cytokine-induced ML NK cells produce greater IFN-γ in response to restimulation and display antitumor activity (pages 881-882).
Fehniger further teaches, “The recent success of chimeric antigen receptor (CAR) T cells in blood cancers also suggests that genetic modification of NK cells with an optimized triggering receptor may be feasible. Proof-of-principle studies have shown that generation of CAR NK cells is possible, but reports using primary human NK cells are limited. Exploration of CAR modification of memory-like and adaptive NK cells is warranted and should potentially be designed for optimal responses based on the biology of memory-like or adaptive NK cells” (page 885).
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to possess an ML NK cell as described by Fehniger comprising a CAR construct such as the anti-CD19 CAR construct taught by Campana, and to administer such a CAR ML NK cell to a subject in need thereof, e.g., a subject having a blood cancer. The skilled artisan would have been motivated to do so because Fehniger teaches that ML NK cells possess antitumor activity which would be valuable in the treatment of cancer, and that the modification of ML NK cells with a CAR may produce more optimal treatment responses. The anti-CD19 CAR construct taught by Campana would further direct the NK cell to the site of a tumor expressing a tumor-associated antigen to allow greater specificity in treating the subject. Furthermore, one of ordinary skill in the art would have recognized that (1) ML NK cells, in comparison to non-memory-like NK cells, have increased functionality and possess antitumor activity, and (2) the art teaches NK cells modified by a CAR. Accordingly, one of ordinary skill in the art would further have recognized that CAR modifications could be similarly and predictably applied to ML NK cells to result in an improved system. See MPEP § 2143(I)(D). There would have been a reasonable expectation of success because CAR NK cells, e.g., the anti-CD19 CAR NK cells disclosed by Campana, have previously been described as having therapeutic utility in treating cancer.
Response to Arguments
Applicant's arguments filed November 19, 2025 have been fully considered but they are not persuasive.
Applicant asserts that Campana does not teach expressing the disclosed CAR in a ML NK cell, and that based on the disclosure of Fehniger, one skilled in the art would not with any certainty have made a CAR-expressing ML NK cell or used them for treatment due to remaining questions concerning the applicability of ML NK cells to cancer treatment. Applicant further submits that the CAR domains encompassed by the instant claims were selected and optimized for ML NK biology (e.g., Figure 5), that the disclosed CAR-ML NK cells exhibit more robust responses (e.g., Figures 2-3), and that anti-CD19 CAR-expressing ML NK cells of the co-pending claims exhibit advanced killing of CD19+ tumor cells (e.g., Figure 7F and ¶ 0199). Applicant submits that these experimental findings could not have been expected from the cited references and outweigh any prima facie obviousness of the instant claims. Remarks at pages 13-15.
In response, it remains held that one of ordinary skill in the art would have had a clear motivation based on the teachings of Fehniger to explore the use of ML NK cells in cancer immunotherapy at least because Fehniger teaches that these cells have anti-tumor properties on their own. Furthermore, Fehniger provides that there are opportunities to enhance ML NK cells responses to cancer, and directly states that “exploration of CAR modification of memory-like … NK cells is warranted” (page 885). With respect to remaining questions on the applicability of memory-like NK cells to cancer treatment, one of the direct questions raised by Fehniger includes “What strategies can be used to target memory NK cells to tumor cells and what is the physiologic in vivo distribution of these cells?” (page 886). Given that Fehniger acknowledges the success of CAR T cells in blood cancers and that proof-of-principle studies have shown that generation of CAR NK cells is possible (page 885), one of ordinary skill in the art would reasonably have been led to consider CARs as a potential strategy for targeted immunotherapy in ML NK cells.
With respect to the experimental findings provided in the disclosure (e.g., Figures 2-3, 5, and 7), it is held that while Applicant states that the CAR constructs were selected and optimized based on ML NK biology, the instantly claimed CAR constructs are not materially (structurally) different from the prior art CAR constructs expressed in non-memory-like NK cells, e.g., as in the CAR-expressing cells disclosed by Campana (e.g., Figure 1). Campana teaches that T cells transduced with the anti-CD19-BB-ζ constructs “were markedly more effective than those lacking 4-1BB signaling”, and that “leukemic cells incubated at a 0.1:1 ratio with lymphocytes expressing anti-CD19-BB-ζ were virtually eliminated in all 5 cultures” (e.g., ¶ 0127-0130). Campana also discloses that IL-2 production was highest in cells expressing the anti-CD19-BB-ζ construct (e.g., ¶ 0131). Thus, one of ordinary skill in the art would have expected that such a CAR construct, comprising an anti-CD19 antigen-binding domain, a CD8α hinge and transmembrane domain, and 4-1BB and CD3ζ intracellular signaling domains, would on its own demonstrate superior tumor killing properties. Further, by the process of routine optimization, one of ordinary skill in the art would be motivated to try an anti-CD19 CAR construct taught by Campana (which Campana demonstrates has favorable tumor-killing properties) in a CAR-ML NK cell (which Fehniger discloses have anti-tumor properties of their own), thereby applying a known technique (i.e., expressing a CAR construct) to a known product ready for improvement (i.e., a CAR-ML NK cell which can be targeted to a tumor cell) to yield a predictable result (i.e., enhanced killing of CD19+ tumor cells). In addition, it is not apparent from Applicant's disclosure whether the instantly claimed CAR-ML NK cells would exhibit significantly enhanced anti-tumor responses compared to CAR-T cells or CAR-NK cells expressing the same anti-CD19 CAR construct, since comparisons among such cells were not made.
For these reasons, the rejection is maintained.
(2)
Claims 49, 53-55, 61, 63, and 68 are rejected under 35 U.S.C. 103 as being unpatentable over Shah (US 2019/0111080 A1; cited in PTO-892 mailed February 11, 2025) in view of Fehniger (Trends in Immunology (2016) 37(12): 877-888; supra). This is a maintained rejection that has been updated based on further consideration of the claims.
Shah teaches chimeric polypeptides (e.g., CARs) comprising an antigen-binding region, a transmembrane region, a spacer region comprising a stalk region(s), and an intracellular signaling domain (¶ 0005-0008). Shah also describes modified effector cells, e.g., NK cells, expressing a polypeptide expressing the CARs of the invention (¶ 0151). Relevant to claims 49, 61, and 63, Shah discloses CARs of the invention comprising (1) an scFv antigen-binding region that binds an epitope on CD19 (¶ 0011, 0016, 0126), (2) at least one costimulatory domain of 4-1BB and/or CD3ζ (¶ 0012), (3) a CD8α hinge domain comprising SEQ ID NO: 107 (¶ 0017, 0092; page 104), for which residues 295-546 share 100% identity to instant SEQ ID NO: 18), and (4) a transmembrane region comprising CD8α (¶ 0121). While not expressly disclosed by Shah, absent a showing otherwise the CAR described by Shah would be capable of being expressed and functioning in a memory-like (ML) NK cell.
Regarding claims 53 and 55, the instant specification sets forth, “NK cells express a number of transmembrane (TM) adapters that signal activation, that are triggered via association with activating receptors. This provides an NK cell specific signal enhancement via engineering the TM domains from activating receptors, and thereby harness endogenous adapters. The TM adapter can be any endogenous TM adapter capable of signaling activation. For example, the TM adapter can be FceR1γ (ITAMx1), CD3ζ (ITAMx3), DAP12 (ITAMx1), or DAP10 (YxxM/YINM)” (page 19). See also Figure 4. The CAR construct taught by Shah, having an anti-CD19 scFv, a CD8α hinge and transmembrane region, and an intracellular signaling domain comprising CD137 and CD3ζ as similarly set forth in the instant claims, would, in view of Applicant's disclosure, form a complex with an endogenous transmembrane adapter such as those set forth in claims 53 and 55. Applicant is reminded that products of identical composition cannot have mutually exclusive properties. A chemical composition and its properties are inseparable. In re Spada 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). See MPEP § 2112.01.
In addition, relevant to claim 68, Shah teaches administering a modified effector cell of the invention to a subject having a cancer associated with overexpression of CD19 (¶ 0021, 0184). Shah also discloses isolating immune effector cells from a subject, introducing a chimeric receptor into the immune effector cell, and rapidly infusing the cells into the subject (¶ 0021, 0253-0254).
However, Shah does not expressly teach a memory-like (ML) NK cell comprising a CAR construct, nor a method of administering such CAR-ML NK cells.
The teachings of Fehniger are recited in the 35 U.S.C. § 103 rejection above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to possess an ML NK cell as described by Fehniger comprising a CAR construct such as the anti-CD19 CAR construct taught by Shah, and to administer such a construct to a subject in need thereof, e.g., a subject having a cancer associated with overexpression of CD19. The skilled artisan would have been motivated to do so because Fehniger teaches that ML NK cells possess antitumor activity which would be valuable in the treatment of cancer, and that the modification of ML NK cells with a CAR may produce more optimal treatment responses. The anti-CD19 CAR construct taught by Shah would further direct the NK cell to the site of a tumor expressing a tumor-associated antigen (e.g., CD19) to allow greater specificity in treating the subject. Furthermore, one of ordinary skill in the art would have recognized that (1) ML NK cells, in comparison to non-memory-like NK cells, have increased functionality and antitumor activity, and (2) the art teaches NK cells modified by a CAR. Accordingly, one of ordinary skill in the art would further have recognized that CAR modifications could be similarly and predictably applied to ML NK cells to result in an improved system. See MPEP § 2143(I)(D). There would have been a reasonable expectation of success because CAR NK cells, e.g., the anti-CD19 CAR NK cells disclosed by Shah, have previously been described as having therapeutic utility in treating cancer.
Response to Arguments
Applicant's arguments filed November 19, 2025 have been fully considered but they are not persuasive.
Applicant asserts that Shah does not teach expressing the disclosed CAR in a ML NK cell, and that based on the disclosure of Fehniger, one skilled in the art would not with any certainty have made a CAR-expressing ML NK cell or used them for treatment due to remaining questions concerning the applicability of ML NK cells to cancer treatment. Applicant further submits that the CAR domains encompassed by the instant claims were selected and optimized for ML NK biology (e.g., Figure 5), that the disclosed CAR-ML NK cells exhibit more robust responses (e.g., Figures 2-3), and that anti-CD19 CAR-expressing ML NK cells of the co-pending claims exhibit advanced killing of CD19+ tumor cells (e.g., Figure 7F and ¶ 0199). Applicant submits that these experimental findings could not have been expected from the cited references and outweigh any prima facie obviousness of the instant claims. Remarks at pages 13-15.
In response, it remains held that one of ordinary skill in the art would have had a clear motivation based on the teachings of Fehniger to explore the use of ML NK cells in cancer immunotherapy at least because Fehniger teaches that these cells have anti-tumor properties on their own. Furthermore, Fehniger provides that there are opportunities to enhance ML NK cells responses to cancer, and directly states that “exploration of CAR modification of memory-like … NK cells is warranted” (page 885). With respect to remaining questions on the applicability of memory-like NK cells to cancer treatment, one of the direct questions raised by Fehniger includes “What strategies can be used to target memory NK cells to tumor cells and what is the physiologic in vivo distribution of these cells?” (page 886). Given that Fehniger acknowledges the success of CAR T cells in blood cancers and that proof-of-principle studies have shown that generation of CAR NK cells is possible (page 885), one of ordinary skill in the art would reasonably have been led to consider CARs as a potential strategy for targeted immunotherapy in ML NK cells.
With respect to the experimental findings provided in the disclosure (e.g., Figures 2-3, 5, and 7), it is held that while Applicant states that the CAR constructs were selected and optimized based on ML NK biology, the instantly claimed CAR constructs are not materially (structurally) different from the prior art CAR constructs expressed in non-memory-like NK cells, e.g., as in the CAR-expressing cells disclosed by Shah. Further, by the process of routine optimization, one of ordinary skill in the art would be motivated to test an anti-CD19 CAR construct taught by Shah in a CAR-ML NK cell (which Fehniger discloses have anti-tumor properties of their own), thereby applying a known technique (i.e., expressing a CAR construct) to a known product ready for improvement (i.e., a CAR-ML NK cell which can be targeted to a tumor cell) to yield a predictable result (i.e., enhanced killing of CD19+ tumor cells). In addition, it is not apparent from Applicant's disclosure whether the instantly claimed CAR-ML NK cells would exhibit significantly enhanced anti-tumor responses compared to CAR-T cells or CAR-NK cells expressing the same anti-CD19 CAR construct, since comparisons among such cells were not made.
For these reasons, the rejection is maintained.
(3)
Claims 49, 54, and 60-61 are rejected under 35 U.S.C. 103 as being unpatentable over Campana (US 2013/0266551 A1; supra) in view of Fehniger (Trends in Immunology (2016) 37(12): 877-888; supra) as applied to claims 49, 53-55, 60, 62-63, and 68 above in (1), and further in view of Shah (US 2019/0111080 A1; supra). This is a maintained rejection.
The teachings of Campana are recited in the 35 U.S.C. § 103 rejection above.
However, Campana does not expressly teach that the CD8α hinge comprised by the CAR of the invention is encoded by the sequence of instant SEQ ID NO: 18.
The teachings of Fehniger, with respect to expressing CARs in ML NK cells, are recited in the 35 U.S.C. § 103 rejection above.
The teachings of Shah, with respect to an anti-CD19 CAR comprising a CD8α hinge that shares sequence identity to the instantly claimed CD8α hinge encoded by instant SEQ ID NO: 18, are recited above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at a ML NK cell expressing an anti-CD19 CAR such as suggested by Campana and Fehniger, comprising a CD8α transmembrane domain encoded by the sequence of instant SEQ ID NO: 19 and a CD8α hinge encoded by the sequence of instant SEQ ID NO: 18 as taught by Shah, through a process of routine optimization. The specific CD8α hinge and CD8α transmembrane domain disclosed by Shah performs materially the same function as the CD8α hinge and CD8α transmembrane comprised by the CAR disclosed by Campana. One of ordinary skill in the art would have recognized that these elements could have been substituted by known methods in the art to construct a CAR in which these elements perform the same function, with predictable results. See also MPEP § 2143(I)(A).
Response to Arguments
Applicant's arguments filed November 19, 2025 have been fully considered but they are not persuasive.
Applicant’s arguments with respect to the deficiencies of Campana and Shah and the teachings of Fehniger, and the Examiner’s response thereto, are summarized above.
(4)
Claims 49, 59-60, 62-64, and 69-70 are rejected under 35 U.S.C. 103 as being unpatentable over Campana (US 2013/0266551 A1; supra) in view of Fehniger (Trends in Immunology (2016) 37(12): 877-888; supra) as applied to claims 49, 53-55, 60, 62-63, and 68 above in (1), and further in view of June (US 2015/0283178 A1; cited in PTO-892 mailed August 19, 2025) and Liu (Journal of Virology (2015) 89(13): 6685-6694; cited in PTO-892 mailed August 19, 2025). This is a maintained rejection that has been updated based on reconsideration of the claims.
The teachings of Campana are recited in the 35 U.S.C. § 103 rejection above.
However, Campana does not teach that the anti-CD19 scFv comprised in the CAR of the invention comprises an anti-CD19 scFv encoded by the nucleic acid sequence of SEQ ID NO: 1.
The teachings of Fehniger are recited in the 35 U.S.C. § 103 rejection above.
June discloses compositions and methods of treatment for cancer (e.g., B-cell malignancies) using immune effector cells (e.g., NK cells) that express an anti-CD19 CAR (e.g., Abstract; ¶ 0006). Relevant to claims 59, 64, and 69-70, June discloses a CD19 CAR construct “CTL019” comprising the amino acid sequence of SEQ ID NO: 58 (Table 7, pages 92-93), for which residues 1-263 share 100% identity to the first 263 residues of the 266-residue translated amino acid sequence of the anti-CD19 scFv encoded by a nucleic acid sequence of instant SEQ ID NO: 1. The translated amino acid sequence of instant SEQ ID NO: 1 is provided in Exhibit A of the Office Action Appendix (mailed August 19, 2025). Residues 1-21 of the CD19 CAR construct correspond to a leader sequence comprising the amino acid sequence of SEQ ID NO: 13 (page 79) and residues 22-263 correspond to an anti-CD19 scFv comprising the amino acid sequence of SEQ ID NO: 59 (Table 7, pages 92-93).
Sequence alignment of translated amino acid sequence corresponding to instant SEQ ID NO: 1 (Qy) and SEQ ID NO: 58 disclosed by June (Db) below:
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345
589
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Greyscale
Liu discloses CAR constructs comprising a tripeptide spacer (“AAA”) which connects the targeting segment (scFv) to the hinge and transmembrane domain (Figure 1, caption). The amino acid sequence of “AAA” shares 100% sequence identity with residues 267-269 of the translated amino acid sequence (same as instantly claimed anti-CD19 scFv encoded by the nucleic acid sequence of SEQ ID NO: 1).
In addition, June discloses that the CD19 CAR constructs of the invention additionally comprise a CD8 transmembrane domain comprising a nucleic acid sequence of SEQ ID NO: 56 (which shares 100% sequence identity to the instantly claimed CD8α transmembrane comprising SEQ ID NO: 19), a 4-1BB (CD137) intracellular domain comprising a nucleic acid sequence of SEQ ID NO: 60 (which shares 100% to the instantly claimed CD137 intracellular signaling domain comprising SEQ ID NO: 22), and a CD3ζ co-stimulatory domain (e.g., pages 3-5; Example 3, pages 79-80). June discloses that the CAR constructs, expressed in T cells, specifically target CD19+ cells and possess cytotoxic activity (e.g., Example 4, pages 94-97). Based on the similarity in the overall structure of the CAR construct disclosed by June relative to that comprised in the instantly claimed CAR-ML NK cells, the CAR disclosed by June would, in view of Applicant's disclosure, form a complex with an endogenous transmembrane adapter such as those set forth in claims 53 and 55. As recited above, products of identical composition cannot have mutually exclusive properties. See MPEP § 2112.01.
Accordingly, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the anti-CD19 CAR-expressing ML NK cell taught by Campana and Fehniger to express a CAR construct comprising an anti-CD19 scFv (same as anti-CD19 scFv that is encoded by the polynucleotide sequence of instant SEQ ID NO: 1) (taught by June and Liu). The skilled artisan would have been motivated to do so because the anti-CD19 CAR taught by June has favorable functional properties for targeting a CD19-expressing B cell malignancy. With respect to the tripeptide linker taught by Liu, it is routine and conventional in the biotechnological art to incorporate and optimize linker sequences in polypeptide constructs. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-CD19 binding domains taught by Campana and June are effectively functional equivalents and that one could be substituted for the other to be used for the same purpose (i.e., targeting a ML NK cell to a CD19-expressing target cell).
Response to Arguments
Applicant's arguments filed November 19, 2025 have been fully considered but they are not persuasive.
Applicant’s arguments with respect to the deficiencies of Campana and Shah and the teachings of Fehniger, and the Examiner’s response thereto, are summarized above. Applicant has not presented any further arguments with respect to June or Liu.
(5)
Claims 49, 53-55, 59-60, 62-64, and 66-70 are rejected under 35 U.S.C. 103 as being unpatentable over June (US 2015/0283178 A1; supra) in view of Fehniger (Trends in Immunology (2016) 37(12): 877-888; supra) and Liu (Journal of Virology (2015) 89(13): 6685-6694; supra). This is a maintained rejection.
The teachings of June, with respect to an anti-CD19 CAR comprising an anti-CD19 scFv, a CD8 transmembrane domain, a CD137 intracellular signaling domain, and a CD3ζ co-stimulatory domain, which can be expressed in NK cells, are recited in the 35 U.S.C. § 103 rejection above.
However, June does not expressly teach that the anti-CD19 scFv comprised in the CAR of the invention is expressed in ML NK cells.
The teachings of Fehniger and Liu are recited in the 35 U.S.C. § 103 rejection above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to possess an ML NK cell as described by Fehniger comprising a CAR construct such as an anti-CD19 CAR construct as taught by June and Liu, and to administer such a CAR ML NK cell to a subject in need thereof, e.g., a subject having a B cell malignancy. The skilled artisan would have been motivated to do so because Fehniger teaches that ML NK cells possess antitumor activity which would be valuable in the treatment of cancer, and that the modification of ML NK cells with a CAR may produce more optimal treatment responses. The anti-CD19 CAR construct would further direct the NK cell to the site of a tumor expressing a tumor-associated antigen to allow greater specificity in treating the subject. Furthermore, one of ordinary skill in the art would have recognized that (1) ML NK cells, in comparison to non-memory-like NK cells, have increased functionality and possess antitumor activity, and (2) the art teaches NK cells modified by a CAR. Accordingly, one of ordinary skill in the art would further have recognized that CAR modifications could be similarly and predictably applied to ML NK cells to result in an improved system. See MPEP § 2143(I)(D). There would have been a reasonable expectation of success because CAR NK cells, e.g., the anti-CD19 CAR NK cells disclosed by June, have previously been described as having therapeutic utility in treating cancer.
Response to Arguments
Applicant's arguments filed November 19, 2025 have been fully considered but they are not persuasive.
Applicant’s arguments with respect to the teachings of Fehniger, and the Examiner’s response thereto, are summarized above. Applicant has not presented any further arguments with respect to June or Liu.
(6)
Claims 49, 54, and 60-61 are rejected under 35 U.S.C. 103 as being unpatentable over June (US 2015/0283178 A1; supra) in view of Fehniger (Trends in Immunology (2016) 37(12): 877-888; supra) and Liu (Journal of Virology (2015) 89(13): 6685-6694; supra) as applied to claims 49, 53-55, 59-60, 62-64, and 66-70 above in (5), further in view of Shah. This is a maintained rejection.
The teachings of June, with respect to an anti-CD19 CAR comprising an anti-CD19 scFv, a CD8 transmembrane domain, a CD137 intracellular signaling domain, and a CD3ζ co-stimulatory domain, which can be expressed in NK cells, are recited in the 35 U.S.C. § 103 rejection above. In addition, June teaches that the anti-CD19 CARs of the invention comprise a CD8 hinge having an amino acid sequence of SEQ ID NO: 14 (Example 3, page 79), which shares 100% sequence identity to residues 40-84 of the 84-residue translated amino acid sequence of the instantly claimed CD8α hinge encoded by the polynucleotide comprising instant SEQ ID NO: 18. For the translated amino acid sequence of instant SEQ ID NO: 18, see Exhibit B of Office Action Appendix (mailed August 19, 2025).
See below for alignment of translated amino acid sequence encoded by instant SEQ ID NO: 18 (Qy) and the CD8α hinge amino acid sequence of SEQ ID NO: 14 disclosed by June (Db):
PNG
media_image2.png
109
587
media_image2.png
Greyscale
However, June does not expressly teach that the anti-CD19 CAR of the invention comprises a CD8α hinge encoded by the full nucleic acid sequence of instant SEQ ID NO: 18.
The teachings of Fehniger and Liu are recited in the 35 U.S.C. § 103 rejection above.
The teachings of Shah, with respect to an anti-CD19 CAR comprising a CD8α hinge that shares 100% sequence identity to the instantly claimed CD8α hinge encoded by instant SEQ ID NO: 18, are recited above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at a ML NK cell expressing an anti-CD19 CAR such as suggested by June, Fehniger, and Liu, comprising a CD8α transmembrane domain encoded by the sequence of instant SEQ ID NO: 19 (as taught by June and Shah) and a CD8α hinge encoded by the sequence of instant SEQ ID NO: 18 (as taught by Shah), through a process of routine optimization. The specific CD8α hinge and CD8α transmembrane domain disclosed by Shah performs materially the same function as the CD8α hinge and CD8α transmembrane comprised by the CAR disclosed by June. One of ordinary skill in the art would have recognized that these elements could have been substituted by known methods in the art to construct a CAR in which these elements perform the same function, with predictable results. See also MPEP § 2143(I)(A).
Response to Arguments
Applicant's arguments filed November 19, 2025 have been fully considered but they are not persuasive.
Applicant’s arguments with respect to the deficiencies of Shah and the teachings of Fehniger, and the Examiner’s response thereto, are summarized above. Applicant has not presented any further arguments with respect to June or Liu.
(7)
Claims 49, 59-60, 62-64, and 68-70 are rejected under 35 U.S.C. 103 as being unpatentable over Shah (US 2019/0111080 A1; supra) in view of Fehniger (Trends in Immunology (2016) 37(12): 877-888; supra) as applied to claims 49, 53-55, 61, 63, and 68 above in (2), and further in view of June (US 2015/0283178 A1) and Liu (Journal of Virology (2015) 89(13): 6685-6694; supra). This is a maintained rejection.
The teachings of Shah are described in the 35 U.S.C. § 103 rejection above.
However, Shah does not teach that the anti-CD19 CAR of the invention comprises an scFv comprising the nucleic acid sequence of instant SEQ ID NO: 1, a transmembrane domain comprising the nucleic acid sequence of instant SEQ ID NO: 19, or a CD137 intracellular signaling domain comprising the nucleic acid sequence of instant SEQ ID NO: 22.
The teachings of Fehniger, with respect to expressing CARs in ML NK cells, are recited in the 35 U.S.C. § 103 rejection above.
The teachings of June and Liu, with respect to an anti-CD19 CAR construct with an anti-CD19 scFv sharing sequence identity to instant SEQ ID NO: 1, a CD8 transmembrane domain sharing sequence identity to SEQ ID NO: 19, and an intracellular signaling domain sharing sequence identity to instant SEQ ID NO: 22, are recited in the 35 U.S.C. § 103 rejection above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the anti-CD19 CAR-expressing ML NK cell taught by Shah and Fehniger to express a CAR construct comprising an anti-CD19 scFv encoded by the polynucleotide sequence of SEQ ID NO: 1, a CD8α transmembrane domain encoded by the polynucleotide sequence of SEQ ID NO: 19, and a CD137 intracellular signaling domain encoded by the polynucleotide sequence of SEQ ID NO: 22 (as taught by June and Liu). The skilled artisan would have been motivated to do so because the anti-CD19 CAR taught by June has favorable functional properties for targeting a CD19-expressing B cell malignancy. With respect to the tripeptide linker taught by Liu, it is routine and conventional in the biotechnological art to incorporate and optimize linker sequences in polypeptide constructs and to optimize transmembrane domains and intracellular signaling domains in a CAR construct. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-CD19 binding domains taught by Shah and June are effectively functional equivalents and that one could be substituted for the other to be used for the same purpose (i.e., targeting a ML NK cell to a CD19-expressing target cell).
Response to Arguments
Applicant's arguments filed November 19, 2025 have been fully considered but they are not persuasive.
Applicant’s arguments with respect to the deficiencies of Shah and the teachings of Fehniger, and the Examiner’s response thereto, are summarized above. Applicant has not presented any further arguments with respect to June or Liu.
Conclusion
No claims are allowed.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643