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 .
Response to Amendment
1. The Amendment filed May 19, 2026 in response to the Office Action of February 19, 2026 is acknowledged and has been entered. Claims 1, 3-4, 6-8, and 10-20 are pending. Claims 2, 5, and 9 are cancelled. Claims 1, 3-4, 6-8, and 10-17 are amended. Claims 1, 3-4, 6-8, and 10-20 are currently being examined.
Rejections Withdrawn
2. The Office Action of February 19, 2026 rejected claims 1-20 under 35 USC 112(a) Written Description. In response to Applicant’s amendment and in light of the new rejection made below necessitated by the amendments, this rejection has been withdrawn.
3. The Office Action of February 19, 2026 rejected claims 13 and 14 under 35 USC 112(b) over indefiniteness. In response to Applicant’s amendment, this rejection is withdrawn.
4. The Office Action of February 19, 2026 rejected claims 1-8 and 10-17 under 35 USC 102(a)(1)(a)(2) as being anticipated by Suri (WO 2018/161017, pub. 9/7/2018) and claims 1, 8-10, and 18-20 under 35 USC 102(a)(1)(a)(2) as being anticipated by Kaufman (US 2018/0002438 A1, pub. 1/4/2018). In response to the Applicant’s amendments, these rejections are withdrawn.
Claim Objections
5. Claim 17 is free of the art but objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. The amino acid sequences of SEQ ID NO: 85 and 108 are novel.
New Rejections
(necessitated by amendments)
Claim Rejections - 35 USC § 112
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.
6. Claims 1, 3-4, 6-8, 10-16, and 18-20 are 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.
Claim 1 recites the limitation "the first self-cleaving peptide", “the first cytokine”, “the second self-cleaving peptide”, and the “second cytokine” in lines 15-17. None of the prior mentioned self-cleaving peptides or cytokines were identified as the first or second. There is insufficient antecedent basis for this limitation in the claim.
Examiner Suggestion: Amend claim 1 to recite “a first self-cleaving peptide”, “a first cytokine”, “a second self-cleaving peptide”, and “a second cytokine”.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
7. Claims 1, 3-4, 6-8, 10-16, and 18-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a WRITTEN DESCRIPTION rejection.
The claims are drawn to a NK CAR polypeptide with an extracellular binding domain that specifically binds to CD19 or CD33 with no listed amino acid structure.
Claim 10 further recites the NK CAR extracellular domain comprising the extracellular binding domain optionally comprising an amino acid sequence that is at least 80% identical to SEQ ID NOs: 35-36.
Thus, the claims identify the NK CAR extracellular binding domains by the function of binding CD19 or CD33 and no sequence structure with dependent claim 10 further identifying the NK CAR extracellular binding domain with the option of comprising the amino acid sequence that is 80% identical to SEQ ID NOs:35-36. Thus, the claims encompass a vast genus of NK CAR polypeptide variants that function to bind CD19 or CD33 with no required amino acid structure.
The instant specification discloses 26 structurally distinct NK CAR cells that function to bind CD19, represented by the polynucleotide sequences of SEQ ID NOs: 45-70 and the polypeptide sequences of SEQ ID NOs: 80-105 that are detailed on the instant specification on pages 65-74 and 79-92.
The instant specification also discloses 9 structurally distinct NK CAR cells that function to bind CD33 represented by the polynucleotide sequences of SEQ ID NOs:71-79 and the amino acid sequences of SEQ ID NOs:106-114 that are detailed on the instant specification on pages 74-78 and 92-96.
Thus, the instant specification identifies structurally distinct NK CAR variants that function to bind CD19 and CD33 and describes the amino acid structure of 26 different NK CARs specifically binding CD19 and 9 different NK CARs specifically binding CD33. The specification fails to disclose any other amino acid sequence structure that possesses the function of binding to CD19 or CD33 or alterations that could be made to the disclosed amino acid sequences and still maintain the ability to function by binding to CD19 or CD33.
To provide adequate written description and evidence of possession of the claimed NK CAR genus, the instant specification can structurally describe representative sequence variants that function to bind CD19 or CD33, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.). A disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.
In this case, the only factor present in the claims is a recitation of the NK CAR function, “specifically binds CD19 or CD33”, and the option of a partial amino acid structure as stated above. The instant specification fails to describe structural features common to the members of the NK CAR genus, which features constitute a substantial portion of the genus, because the instant specification fails to disclose representative NK CAR variant sequences that function as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the NK CAR does, rather than what it is. Other than the NK CARs disclosed in the polynucleotide sequences of SEQ ID NOs:45-79 and the amino acid sequences of SEQ ID NOs:80-114 on pages 65-96, the specification fails to provide structural features coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of NK CAR sequence variants for the genus of NK CARs that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to make the claimed NK CARs that specifically bind CD19 or CD33.
The claims broadly encompass any NK CAR that functions to bind CD19 or CD33. Applicants have not established any reasonable structure-function correlation with regards to the sequences of the disclosed NK CAR cells that can be altered and still maintain CD19 or CD33 binding. Given the well-known high level of polymorphism of antigen binding sequences and structure, the skilled artisan would not have been in possession of the vast repertoire of NK CAR encompassed by the claimed invention. One could not reasonably or predictably extrapolate the structure of a single NK CAR to the structure of any variants required to bind CD19 or CD33 as broadly claimed. Therefore, one could not readily envision members of the broadly claimed genus.
Although Applicants may argue that it is possible to screen for binding domains that bind CD19 or CD33 and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future NK CARs specifically binding CD19 or CD33 yet to be discovered that may function as claimed. The CD19 and CD33 antigen provides no information about the structure of a binding domain that binds to it.
Given the lack of representative examples to support the full scope of the claimed CD19 or CD33 NK CAR genus, and lack of reasonable structure-function correlation with regards to the unknown variable sequences in the binding domains that provide CD19 or CD33-binding function, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of NK CARs that specifically bind CD19 or CD33 that is required to practice the claimed invention.
Examiner Suggestion: Examiner suggests amending claim 1 to recite:
“a) an extracellular binding domain, wherein the extracellular binding domain specifically binds to CD19 or CD33, wherein the extracellular binding domain comprises an amino acid sequence identical to one of SEQ ID NOs: 35-36;”
Response to Arguments
8. Applicant traverses the rejection of claims 1-20 under 35 U.S.C. 112(a) because amended claim 1 explicitly specifies the composition and order of intracellular domain elements: co-stimulatory domain 4-1BB, signaling domain FcεR1, self-cleaving peptides, dual cytokines IL-15 and IL-21 and specific targeting for CD19 or CD33.
Applicant's arguments filed on May 29, 2026 have been fully considered but they are not persuasive. The amendments to claim 1 have provided a new reason for rejection of the claims under 35 U.S.C. 112(a), specifically for written description. In response, the new rejection above has been entered.
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.
9. Claims 1, 3-4, 6, 8, 10-16, and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Suri (WO2018/161017 pub. 9/7/2018) in view of Boissel (WO 2019/226708 A1, pub. 11/28/2019) and Batra (Cancer Immunology Res., 2020, 8(3):309-320) and Strengell (J Immunol., 2003, 170(11):5464-5469) and Chmielewski (Adv. Cell Gene Ther., 2020, 3:e84).
Suri discloses a chimeric antigen receptor (CAR) polypeptide for expression in natural killer cells comprising from N-terminus to C-terminus an extracellular binding domain, including the CD19 extracellular binding domain amino acid sequence of SEQ ID NO:35, a transmembrane domain of CD8, including the CD8 intracellular transmembrane domain amino acid sequence of SEQ ID NO: 32, an intracellular domain comprising an intracellular signaling domain, including the intracellular signaling domain of FcεR1 amino acid sequence of SEQ ID NO: 12, and an intracellular co-stimulatory domain of 4-1BB, including the co-stimulatory domain of 4-1BB amino acid sequence of SEQ ID NO: 15. (See pg. 4 [0016], also alignments below). Suri also discloses the use of P2A as a self-cleaving peptide that is represented by the amino acid sequence of SEQ ID NO: 19. (See Suri, pg. 133, [298], also alignment below).
Regarding claims 11-16, Suri teaches a signal peptide can be located on the N-terminus of the extracellular binding domain and includes the disclosure of the CD8 signal peptide that 100% matches SEQ ID NO: 38. (See Suri, pg. 127 [00272], also alignment below). Suri also teaches detectable markers and linker domains that can be located between the extracellular domain and the signal peptide. (See Suri, pg. 19 [00121], also Fig. 2A). Suri also teaches CAR constructs comprising a spacer region located between the extracellular binding domain and the transmembrane domain, including a CD8 hinge domain comprising the amino acid sequence of SEQ ID NO: 44. (See Suri, pg. 67 [00222], also alignments below).
Suri does not disclose the intracellular signaling domain of FcεR1 being used within an active CAR construct or the intracellular domain comprising two self-cleaving peptides and two cytokines, IL-15 and IL21, wherein the self-cleaving peptides and cytokines are arranged from the transmembrane domain: first cleaving peptide, first cytokine, second self-cleaving peptide, and second cytokine.
Boissel discloses a NK CAR cell comprising a FcεR1 signaling domain. (See Boissel, claim 1). Boissel teaches that CAR NK cells using FcεR1 as a signaling domain have significantly increased expression of the NK CARs and extended cytotoxicity over time over the traditional CD3ζ signaling domain, effectively creating a population of NK CAR cells that after contacting other NK cells will increase activation. (See Boissel, pg. 5 [015]). Boissel also teaches the method of treating a subject in need of a CAR based therapy by administering the NK CAR to the subject in a therapeutically effective amount. (See Boissel, pg. 27 [048]).
Boissel does not teach the intracellular domain of two self-cleaving peptides and two cytokines, IL-15 and IL-21.
Batra teaches a CAR polypeptide for expression in a T-cell that co-expresses IL-15 and IL-21 with the self-cleaving peptide T2a included between the CAR polypeptide and the two cytokines. (See Batra, pg. 310 “Generation of Retroviral constructs” also Fig. 1A below). Batra further teaches that CAR-T cells co-expressed with IL15 and IL-21 observed synergistic effect in effector cytokine production, expansion, and anti-tumor activity over CAR cells expressing one cytokine or controls. (See Batra, pg. 317 “Discussion”).
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377
1108
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Batra teaches a CAR-T cell that is co-expressed with two cytokines but does not teach a CAR NK cell expressed with two cytokines and two self-cleaving peptides as a part of the intracellular signaling domain.
Strengell teaches that IL-21 has a synergistic effect with IL-15 in both human T cells and NK cells. (See Strengell, abstract).
Chmielewski teaches 4th generation CAR T cells that co-express cytokines to initiate activation strategically places the self-cleaving peptides and cytokines on the intracellular signaling domain for cytokine release to occur upon stimulation of a CAR cell with a target antigen. (See Chmielewski, pg. 2, column 1, paragraph 2).
It would have been prima facie obvious for a person of ordinary skill in the art prior to the effective filing date to use the disclosed sequences and parts of the CAR polypeptide of Suri along with the FcεR1 intracellular signaling domain of Boissel. It would have been obvious because Boissel teaches that FcεR1 signaling domains significantly increase expression of NK CARs over the traditional CD3ζ intracellular signaling domain. It would have had a reasonable expectation of success because Boissel had used the FcεR1 signaling domain in a NK CAR cell and already observed that the NK CAR had increased potency over the traditional CD3ζ intracellular signaling domain traditionally used with CAR-T cells. Therefore, it would have been obvious to a person of ordinary skill in the art to use the CAR disclosed in Suri with the intracellular signaling domain of Boissel with a reasonable expectation of successfully producing the NK CAR cell of the presently claimed invention.
It would have been prima facie obvious for a person of ordinary skill in the art prior to the effective filing date to combine the CAR construct of Suri and Boissel with the CAR peptide design of Batra with the teachings of Strengell and Chmielewski to produce the CAR NK of the present claimed invention. It would have been obvious because Batra teaches the CAR T cell co-expressed with IL-15 and IL-21 observed synergistic effects in expansion, cytokine release, and anti-tumor control and Strengell teaches that synergistic effects of IL-21 and IL-15 are observed in both T cells and NK cells. It would have a reasonable expectation of success because Batra already successfully produce a CAR T cell showing enhanced T cell function with anti-tumor activity and while the Batra construct placed the cytokine with self-cleaving peptides on the N-terminus side of the extracellular domain Chmielewski teaches that it is advantageous for CAR cells to express the cytokines on the intracellular signaling domains to use target antigen contact to initiate cytokine expression to bolster CAR cell activation and proliferation. Therefore, it would have been prima facie obvious to use the CAR construct of Suri and Boissel with the co-expressed cytokines as taught by Batra, Strengell, and Chmielewski with a reasonable expectation of success at producing the CAR NK polypeptide of the presently claimed invention.
SEQ ID NO: 35 is 100% identical to SEQ ID NO: 232 (Suri):
WO2018161017-A1.
XX
CC PD 07-SEP-2018.
XX
CC PF 02-MAR-2018; 2018WO-US020741.
XX
PR 03-MAR-2017; 2017US-0466601P.
PR 11-APR-2017; 2017US-0484052P.
XX
CC PA (OBSI-) OBSIDIAN THERAPEUTICS INC.
XX
CC PI Suri V, Briskin MJ, Dolinski B, Elpek KG, Li DJ, Heller SF;
CC PI Ols ML, Sun D, Kosmider N, Kulkarni A, Balakrishnan V, Ezell T;
XX
DR WPI; 2018-706735/63.
XX
CC PT Composition useful for inducing immune response, and reducing tumor
CC PT volume or burden, comprises first effector module including first
CC PT stimulus response element operably linked to immunotherapeutic agent.
XX
CC PS Claim 14; SEQ ID NO 232; 313pp; English.
XX
%
Result Query Filing
No. Score Match Length ID Date Dups Description
-------------------------------------------------------------------------------------------------------------
1 1279 100.0 242 AZX24807 -- 536 Murine anti-CD19 antibody scFv SEQ ID NO:20.
ALIGNMENT:
Query Match 100.0%; Score 1279; Length 242;
Best Local Similarity 100.0%;
Matches 242; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPS 60
Qy 61 RFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGGGGSGGGGSGGG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGGGGSGGGGSGGG 120
Qy 121 GSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTY 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTY 180
Qy 181 YNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTV 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 YNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTV 240
Qy 241 SS 242
||
Db 241 SS 242
SEQ ID NO: 32 is 100% identical to SEQ ID NO: 505 (Suri):
PNG
media_image2.png
346
454
media_image2.png
Greyscale
PNG
media_image3.png
135
455
media_image3.png
Greyscale
SEQ ID NO: 12 is 100% identical to SEQ ID NO: 373 (Suri):
PN WO2018161017-A1.
XX
CC PD 07-SEP-2018.
XX
CC PF 02-MAR-2018; 2018WO-US020741.
XX
PR 03-MAR-2017; 2017US-0466601P.
PR 11-APR-2017; 2017US-0484052P.
XX
CC PA (OBSI-) OBSIDIAN THERAPEUTICS INC.
XX
CC PI Suri V, Briskin MJ, Dolinski B, Elpek KG, Li DJ, Heller SF;
CC PI Ols ML, Sun D, Kosmider N, Kulkarni A, Balakrishnan V, Ezell T;
XX
DR WPI; 2018-706735/63.
XX
CC PT Composition useful for inducing immune response, and reducing tumor
CC PT volume or burden, comprises first effector module including first
CC PT stimulus response element operably linked to immunotherapeutic agent.
XX
CC PS Claim 17; SEQ ID NO 373; 313pp; English.
%
Result Query Filing
No. Score Match Length ID Date Dups Description
-------------------------------------------------------------------------------------------------------------
10 215 100.0 66 BCL31207 -- 8 IgE Fc-Receptor gamma signaling domain protein SEQ ID NO:12.
ALIGNMENT:
Query Match 100.0%; Score 215; Length 66;
Best Local Similarity 100.0%;
Matches 42; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 RLKIQVRKAAITSYEKSDGVYTGLSTRNQETYETLKHEKPPQ 42
||||||||||||||||||||||||||||||||||||||||||
Db 25 RLKIQVRKAAITSYEKSDGVYTGLSTRNQETYETLKHEKPPQ 66
SEQ ID NO: 15 is 100% identical to SEQ ID NO: 273 (Suri):
PNG
media_image4.png
358
448
media_image4.png
Greyscale
PNG
media_image5.png
267
667
media_image5.png
Greyscale
SEQ ID NO: 38 is 100% identical to SEQ ID NO: 628 (Suri):
PNG
media_image6.png
365
457
media_image6.png
Greyscale
PNG
media_image7.png
278
792
media_image7.png
Greyscale
SEQ ID NO: 44 100% matches SEQ ID NO: 411 (Suri):
PNG
media_image8.png
773
466
media_image8.png
Greyscale
SEQ ID NO: 19 100% matches SEQ ID NO: 725 (Suri):
WO2018161017-A1.
XX
CC PD 07-SEP-2018.
XX
CC PF 02-MAR-2018; 2018WO-US020741.
XX
PR 03-MAR-2017; 2017US-0466601P.
PR 11-APR-2017; 2017US-0484052P.
XX
CC PA (OBSI-) OBSIDIAN THERAPEUTICS INC.
XX
CC PI Suri V, Briskin MJ, Dolinski B, Elpek KG, Li DJ, Heller SF;
CC PI Ols ML, Sun D, Kosmider N, Kulkarni A, Balakrishnan V, Ezell T;
XX
DR WPI; 2018-706735/63.
DR N-PSDB; BFQ52086.
XX
CC PT Composition useful for inducing immune response, and reducing tumor
CC PT volume or burden, comprises first effector module including first
CC PT stimulus response element operably linked to immunotherapeutic agent.
XX
CC PS Disclosure; SEQ ID NO 725; 313pp; English.
XX
CC The present invention relates to a novel composition for inducing an
CC immune response in a cell or a subject. The composition comprises a first
CC effector module, where the effector module comprises a first stimulus
CC response element (SRE) operably linked to at least one immunotherapeutic
CC agent (chimeric antigen receptor, antibody). The invention also provides:
CC a polynucleotide encoding the fusion polypeptide; a vector comprising the
CC polynucleotide; an immune cell for adoptive cell transfer (ACT); a method
CC for reducing a tumor volume or burden in a subject; a method for inducing
CC an immune response in a subject; a method for identifying a domain of a
CC CD19 antigen which will not bind the FMC63 antibody (FMC63-distinct CD19
CC binding domain); a chimeric antigen receptor comprising the FMC63-
CC distinct CD19 binding domain; and an effector module comprising the SRE
CC linked to the chimeric antigen receptor. The composition is useful for
CC treating cancer and infectious diseases. The present sequence represents
CC a DD IL15 fusion construct, which can be useful for preparing the
CC composition of the invention.
XX
SQ Sequence 389 AA;
Query Match 100.0%; Score 115; Length 389;
Best Local Similarity 100.0%;
Matches 22; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GSGATNFSLLKQAGDVEENPGP 22
||||||||||||||||||||||
Db 133 GSGATNFSLLKQAGDVEENPGP 154
10. Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Suri (WO2018/161017 pub. 9/7/2018) in view of Boissel (WO 2019/226708 A1, pub. 11/28/2019) and Batra (Cancer Immunology Res., 2020, 8(3):309-320) and Strengell (J Immunol., 2003, 170(11):5464-5469) and Chmielewski (Adv. Cell Gene Ther., 2020, 3:e84) as applied to claims 1, 3-4, 6, 8, 10-16, and 18-20 above, and further in view of Wang (CN108219004A, pub. 6/29/2018).
Suri, Boissel, Batra, Strengell, and Chmielewski disclose the limitations of claim 1 as discussed above.
Suri, Boissel, Batra, Strengell, and Chmielewski does not disclose the IL-15 cytokine of the NK CAR peptides as comprising the amino acid sequence of SEQ ID NO:23.
Wang teaches a CAR T cell that encodes a self-cleaving peptide followed by a IL-15 cytokine that co-expresses along with the CAR protein for the purposes of stimulating the activation of the CAR-T cells. (See Wang, pg. 5 [0012]; pg. 11 [0046]). Wang discloses an IL-15 amino acid sequence that matches SEQ ID NO: 23. (See alignment below).
It would have been prima facie obvious for a person of ordinary skill in the art prior to the effective filing date to use the CAR NK of Suri, Boissel, Batra, Strengell, and Chmielewski with the IL-15 amino acid sequence disclosed in Wang to produce the NK CAR of the present claimed invention. It would have been obvious because Wang teaches that the IL-15 co-expressed can be used to stimulate the activation of the CAR T cells. It would have a reasonable expectation of success because Wang disclosed the amino acid sequence of SEQ ID NO: 23 was successfully used to produce a CAR T cell that co-expressed IL-15 and stimulated CAR T cells to activate. Therefore, it would have been obvious for a person of ordinary skill in the art prior to the effective filing date to use the CAR NK cell of Suri, Boissel, Batra, Strengell, and Chmielewski with the amino acid sequence of IL-15 disclosed in Wang with a reasonable expectation of success at producing the NK CAR of the present claimed invention.
SEQ ID NO:23 100% matches SEQ ID NO: 20 (Wang):
CN108219004-A.
XX
CC PD 29-JUN-2018.
XX
CC PF 08-FEB-2018; 2018CN-10127130.
XX
PR 08-FEB-2018; 2018CN-10127130.
XX
CC PA (JILI-) JILIN TUOHUA BIOLOGICAL TECHNOLOGY CO.
XX
CC PI Wang B, Xu Y, Bi W;
XX
DR WPI; 2018-533660/59.
DR N-PSDB; BFM26338.
XX
CC PT New bispecific chimeric antigen receptor useful for producing T
CC PT lymphocyte, for preparing antitumor medicine, comprises chimeric antigen
CC PT receptor part that specifically binds to e.g. carcinoembryonic antigen 5
CC PT extracellular region.
XX
CC PS Disclosure; SEQ ID NO 20; 32pp; Chinese.
%
Result Query Filing
No. Score Match Length ID Date Dups Description
-------------------------------------------------------------------------------------------------------------
1 833 100.0 162 AAB18632 -- 607 Amino acid sequence of a human interleukin-4 helix A fragment.
ALIGNMENT:
Query Match 100.0%; Score 833; Length 162;
Best Local Similarity 100.0%;
Matches 162; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MRISKPHLRSISIQCYLCLLLNSHFLTEAGIHVFILGCFSAGLPKTEANWVNVISDLKKI 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MRISKPHLRSISIQCYLCLLLNSHFLTEAGIHVFILGCFSAGLPKTEANWVNVISDLKKI 60
Qy 61 EDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANN 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 EDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANN 120
Qy 121 SLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS 162
||||||||||||||||||||||||||||||||||||||||||
Db 121 SLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINTS 162
Response to Relevant Arguments
11. Applicant argues that the claims are amended and limited to a CAR that comprises: anti-CD19 or CD33 binding domain + 4-1BB + a high affinity IgE receptor FcεR1 intracellular signaling domain + two self-cleaving peptides + IL-15 + IL-21. Applicant argues that Suri does not teach or suggest the specific combination of claimed CAR components. Applicant argues that Suri lists FcεR1 and CD3ζ as alternatively selected signaling domains but does not compare the superiority of the two. Applicants argue that Examples 2, 4, 5, and 6 of the instant specification demonstrate FcεR1 is technically superior to CD3ζ in NK cells and this is an unexpected property not taught by the cited prior art. Applicant argue that the cited prior art does not disclose the synergistic effect of IL-15 and IL-21. Applicants argues that Suri mentions IL-15 as a cytokine option but does not disclose IL-21. Applicant argues the claimed CAR produces unexpected synergistic activation effects in NK cells, including:
(1) Enhanced cytotoxic activity;
(2) High-level cytokine release; and
(3) Specific killing of tumor cells.
Applicant argues a person of ordinary skill in the art would not have reason or motivation to modify the CAR disclosed in Suri to arrive that the instantly claimed CAR.
The arguments have been considered but are not persuasive. Contrary to arguments, the cited combined references with Suri teach and render obvious all of the claimed CAR elements that are known and routinely used to construct CARs, for the reasons stated in the new rejection of claims under 35 USC 103. With regards to superior activity and unexpected synergistic activation of NK cells expressing the claimed CAR, Applicant is arguing limitations not recited in the claims. Claim 1 recites an intended use of the CAR “for expression in natural killer cells (NK) cells”, however, the claims do not require or recite any NK cells actually expressing the CAR. Applicant has argued unexpected synergistic and superior results as a result of NK cells expressing the CAR, which is not recited in the claims.
MPEP 716.02(d) states: Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range.
In the instant case, Applicants have argued unexpected results and superior properties for NK cells expressing the claimed CAR. The claims do not recite or require an NK cell expressing the claimed CAR, therefore the unexpected results and superior properties argued by Applicant are not commensurate in scope with the instantly claimed invention.
12. Conclusion: Claim 17 is objected to. Claims 1, 3-4, 6-8, 10-16, and 18-20 are rejected.
Conclusion
13. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/LINDSAY DUNN/ Examiner, Art Unit 1644
/Laura B Goddard/Primary Examiner, Art Unit 1642
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