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 .
Priority
This application is a U.S. national phase of International Application No. PCT/US2022/011319, filed on 01/05/2022, which claims domestic benefit to US provision application 63/134,152, filed 01/05/2021.
Claim Status
The Amendment, filed on 07/05/2023, is acknowledged in which:
Claims 5, 8-14, 16-17, 20, 26, 30-35, 37-39, and 41 are canceled.
Claims 6-7, 15, 18-19, 21-25, 27-28 are currently amended.
Claims 1-4, 29, 36, and 40 are original.
Claims 1-4, 6-7, 15, 18-19, 21-25, 27-29, 36, 40, and 42 are pending in the instant application and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement filed 07/05/2024 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. NPL reference “GenBank…XP_016862885.1” (#53) has been placed in the application file, but the information referred to therein has not been considered. All other references, where not lined through, have been considered.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing (Figure 4A) executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2)
Otherwise, Examiner recommends amending the figure to a single color gradient instead of the current dual color gradient to distinguish negative from positive heatmap values.
Specification
The disclosure is objected to because of the following informalities:
“Clb-b” should read “Cbl-b” (pg 2, ¶ 3, line 8; pg 5, ¶ 3, line 6)
“ewing” should be capitalized (pg 8, line 15; pg 23, line 6)
“compaerd" should read “compared” (pg 32, second to last line)
Appropriate correction is required.
The use of the term “Ficoll” (pg 9, ¶ 2, line 12), “Ficoll-Paque” (pg 27, line 1), “TexMACS” (pg 17, ¶ 2, line 1; pg 17, ¶ 3, line 7), “CellGro” (pg 17, ¶ 3, line 7), “AIM-V” (pg 17, ¶ 3, line 8), “Accell” (pg 27, ¶ 3, line 8; pg 27, ¶ 4, lines 1 and 2; pg 28, ¶ 4, line 2), “RNeasy” (pg 27, ¶ 5, line 2) “SYBR” (pg 27, last line), “IRDye” (pg 28, ¶ 2, line 5), “LSRFortessa” (pg 28, ¶ 5, line 3; pg 29, line 2), “GolgiPlug” (pg 28, ¶ 5, line 4; pg 29, line 3), “Cytofix/Cytoperm” (pg 29, line 1), “FlowJo” (pg 29, line 4 which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 4 and 27 are objected to because of the following informalities:
Claim 4, line 2: “Clb-b” should read “Cbl-b”.
Claim 27, line 2: “ewing” should be capitalized
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 21 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.
The specification defines inhibitory oligonucleotides as an antisense oligonucleotide (ASO), an shRNA, or an siRNA (pg 6, lines 17-19). These silencing oligos are typically complimentary to RNA transcripts and not directly to the gene (i.e. DNA sequence SEQ ID NO:3) nor the amino acid sequence (SEQ ID NOs: 4-32). As these terms are used contrary to their ordinary meaning the claim is unclear and therefore renders the claim indefinite. For examination purposes, examiner has interpreted the claim as follows (presented to applicant for consideration):
The method of claim 19, wherein the inhibitory oligonucleotide is complimentary to at least 8-20 continuous nucleotides of an RNA transcript, wherein the RNA transcript (a) is derived from a gene encoding Cbl-b or SEQ ID NO:3, or (b) encodes a protein comprising a sequence selected from SEQ ID NOs: 4-32.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 1 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more. A three-step inquiry has been established to determine subject matter eligibility under 35 U.S.C. 101, in accordance with MPEP § 2106(III):
Step (1): Is the claim directed to a process, machine, manufacture, or composition of matter?
Yes. The claims are drawn to a composition of NK cells that do not express Cbl-b or have reduced or suppressed expression of Cbl-b.
Step (2A) Prong 1: Is the claim directed to a law of nature, natural phenomenon (product of nature), or an abstract idea?
Yes. The claim is drawn to a genus of NK cells with reduced or no Cbl-b expression. This genus by broadest reasonable interpretation includes NK cells that have reduced Cbl-b expression as a result of a naturally occurring mutation observed in patients (e.g. p.R496X in which abolished CBL-B expression and p.H285L in which CBL-B expression was half the normal level) as disclosed by Janssen (J Clin Invest. 2022;132(20):e154487) (Abstract).
Step (2A) Prong 2: If the claim recites a judicial exception, does it recite additional elements that integrate the judicial exception into a practical application?
No. Claim 1 does not recite additional elements that integrate the judicial exception into a practical application.
Step (2B): If the recited judicial exception is not integrated into a practical application, does the claim recite additional elements that amount to significantly more than the judicial exception?
No. Claim 1 does not include additional elements that are sufficient to amount to significantly more than the judicial exception because isolated cells from patients is well-understood, routine, and conventional in the art and the cells could be naturally derived (e.g. from patients with naturally occurring Cbl-b mutations) without any characteristics that differentiate it from Cbl-b mutant NK cells as they exist in nature.
As the instant claims recite judicial exceptions and claim an eligible population of patients for which the judicial exception is not integrated into practical application, and no elements that amount to significantly more than the judicial exception are recited, the claims were found to not be drawn to eligible subject matter under 35 USC 101.
Claim Rejections - 35 USC § 102
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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-4, 6-7, 15, 18, 23, 40, and 42 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2020/247392 A1 (herein Trager) as evidenced by Guo (J Immunother Cancer. 2021;9(3):e001975).
Trager teaches CBLB knockout NK cells using CRISPR/Cas9 guided by CBLB-targeting guide RNA (i.e. gene editing) (¶ [00300]-[00302]; SEQ ID NOs: 164-165). SEQ ID NO:164 is inherently sufficient to ablate CBLB expression in primary NK cells as evidenced by Guo (Figure 1D; pg 4, left column, ¶ 2). Trager teaches a method of generating said knockout cells using parent NK cells (i.e. obtained population of NK cells) maintained in culture with feeder cells (K562 cells expressing, for example, 41BBL and/or mbIL15; ¶ [00279]) for 7 days, electroporating cells, incubating for several days with IL-2 media before using in tumor challenge assays (i.e. expanded population of CBLB negative NK cells). Trager teaches CBLB knockout has a positive impact on NK cell cytotoxicity against Reh cells, suggesting CBLB knockout can be employed in conjunction with other engineering (i.e. CAR expression (Figure 14D) or additional knockouts) to further enhance NK cell cytotoxicity and/or persistence for cancer treatment (Figure 23C; ¶ [00302]).
Claims 1-4, 6-7, 15, 18-19, 21, and 40 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 9,186,373 B2 (herein Lametschwandtner) as evidenced by NIH basic local alignment search tool (BLASTn).
Lametschwandtner teaches Cbl-b inhibition in NK cells using siRNA and antisense oligonucleotides (ASOs) (i.e. inhibitory oligonucleotides) targeting Cbl-b transcripts (Examples 1 and 2) (SEQ ID NOs: 1-4, which are complementary to transcripts encoding instant SEQ ID NOs: 4-31 as evidenced by BLASTn results, summarized in the table below). Lametschwandtner teaches methods of transfection involving isolating NK cells from PBMCs (i.e. obtaining a population of NK cells), transfecting cells, and culturing cells for functional assays (Example 2). Lametschwandtner also teaches co-culture with K562 cells (i.e. feeder cells) (Example 3; Figures 2-3).
Instant
GenBank Accession Number
Lametschwandtner SEQ ID NO:
SEQ ID NO:
Protein ID (Spec pg 3)
Coding Transcript ID
1
2
3
4
4
XP_011511559.1
XM_011513257
+
+
+
+
5
XP_016862884.1
XM_017007395
+
+
+
+
6
XP_016862887.1
XM_017007398
+
+
+
+
7
NP_001308719.1
NM_001321790
+
+
+
+
8
XP_016862888.1
XM_017007399
-
-
-
-
9
NP_001308725.1
NM_001321796
+
+
+
+
10
NP_001308735.1
NM_001321806
+
+
+
+
11
NP_001308726.1
NM_001321797
-
-
+
+
12
NP_001308723.1
NM_001321794
-
-
+
+
13
NP_001308720.1
NM_001321791
+
+
+
+
14
NP_001308717.1
NM_001321788
+
+
+
+
15
NP_001308737.1
NM_001321808
+
+
+
+
16
NP_001308749.1
NM_001321820
+
+
+
+
17
NP_001308728.1
NM_001321799
+
+
+
+
18
NP_001308745.1
NM_001321816
-
-
+
+
19
NP_001308740.1
NM_001321811
-
-
+
+
20
NP_001308727.1
NM_001321798
-
-
+
+
21
NP_001308724.1
NM_001321795
-
-
+
+
22
NP_001308722.1
NM_001321793
+
+
+
+
23
NP_733762.2
NM_170662
+
+
+
+
24
NP_001308751.1
NM_001321822
+
+
+
+
25
NP_001308736.1
NM_001321807
+
+
+
+
26
XP_016862889.1
XM_017007400
+
+
+
+
27
XP_016862886.1
XM_017007397
+
+
+
+
28
XP_016862885.1
XM_017007396
+
+
+
+
29
NP_001308715.1
NM_001321786
+
+
+
+
30
NP_001308718.1
NM_001321789
-
-
+
+
31
NP_001308742.1
NM_001321813
-
-
+
+
Claims 1-3, 23, 36, 40, and 42 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 12,012,458 B2 (herein Trager-2)
Trager-2 teaches a population of engineered immune cells (comprising NK cells - claim 9), expanded in culture, expressing a CAR comprising a tumor binding domain that targets CD70, and are genetically edited to reduce CBLB expression (claims 6, 7, 9, 12, 13). Reduced expression is defined as a reduction in expression of target protein by about 30% or more (i.e. within scope of the instant range) (column 47, last ¶).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Lametschwandtner as applied to claim 19 above, and further in view of Revvity (statement regarding CBLB siRNA) as evidenced by Horizon (Accell siRNA product page, catalog No. A-003004-20).
Lametschwandtner teaches claim 19 as discussed above.
Lametschwandtner does not teach an inhibitory oligonucleotide comprising SEQ ID NO:1
Revvity teaches a human CBLB targeting siRNA (i.e. inhibitory oligonucleotide) identical to SEQ ID NO:1 (catalog # A-003004-20) as on sale before the effective filing date of the claimed invention (since Aug 5, 2007), which targets CBLB transcripts which encode instant SEQ ID NOs: 4-31 (protein accession numbers disclosed in the instant specification - pg 3) as evidenced by Horizon (“Targets” pg 2-3; summarized in table below)
SEQ ID NO:
GenBank Accession Number
Protein ID
Coding Transcript ID
4
XP_011511559.1
XM_011513257
5
XP_016862884.1
XM_017007395
6
XP_016862887.1
XM_017007398
7
NP_001308719.1
NM_001321790
8
XP_016862888.1
XM_017007399
9
NP_001308725.1
NM_001321796
10
NP_001308735.1
NM_001321806
11
NP_001308726.1
NM_001321797
12
NP_001308723.1
NM_001321794
13
NP_001308720.1
NM_001321791
14
NP_001308717.1
NM_001321788
15
NP_001308737.1
NM_001321808
16
NP_001308749.1
NM_001321820
17
NP_001308728.1
NM_001321799
18
NP_001308745.1
NM_001321816
19
NP_001308740.1
NM_001321811
20
NP_001308727.1
NM_001321798
21
NP_001308724.1
NM_001321795
22
NP_001308722.1
NM_001321793
23
NP_733762.2
NM_170662
24
NP_001308751.1
NM_001321822
25
NP_001308736.1
NM_001321807
26
XP_016862889.1
XM_017007400
27
XP_016862886.1
XM_017007397
28
XP_016862885.1
XM_017007396
29
NP_001308715.1
NM_001321786
30
NP_001308718.1
NM_001321789
31
NP_001308742.1
NM_001321813
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed that the siRNA method as taught by Lametschwandtner could substituted with the siRNA sequence as taught by Revvity with a reasonable expectation of targeting sequences encoding the instantly claimed sequences because Revvity teaches this siRNA as suitable to target human CBLB which targets transcripts within scope of the instant claim as evidenced by Horizon (“The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945)”; See MPEP 2144.07).
Claims 24-25, 27, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Trager (cited above) as applied to claim 2.
Trager teaches claim 2 as discussed above.
Trager further teaches dual CD19-CAR and CISH (negative regulator of IL-15 signaling, where IL-15 signaling is necessary for NK cell expansion, survival and cytotoxicity - ¶ [00290]) knockout NK cells have synergistic effects toward cytotoxicity against Nalm6 cells (leukemia model cell line) in culture (Figure 21B). Trager teaches CBLB is also a negative regulator of NK activation (¶ [0053]), and CBLB KO has a positive effect on NK cell cytotoxicity on REH cells (leukemia model cell line) proportionate to CISH KO NK cells (Figure 23A). Trager further teaches CAR targets can be tailored for various antigens including cancer antigens and viral antigens (¶ [00275]).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to that CISH KO could be substituted in CAR-NK cells as taught by Trager because Trager also teaches CBLB KO has proportionate effects to CISH KO regarding NK cell cytotoxicity. Further a skilled artisan would be motivated to combine CBLB KO NK cells with a tumor targeting CAR as Trager teaches dual strategies result in a synergistic improvement to NK cell activation in the context of cancer or viral infection.
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over US 11,242,530 B2 (herein Yu) and Lametschwandtner (cited above) and Trager (cited above).
Yu teaches the feasibility of cloning a CAR and siRNA within a single recombinant lentiviral vector (Figure 4; Example 1). Yu specifically teaches a vector comprising a BCMA-CAR and PD-1 (immune checkpoint molecule) siRNA for infection of PBMCs (Embodiment 3). Yu observed that cells with successful CAR expression and knockdown of PD-1 had improved cytotoxicity (species 1453 and 1454 in Figures 11, 13, and 14).
Lametschwandtner teaches CBLB silencing via siRNA in NK cells improves NK cell activation (Figures 1-4).
Trager teaches combination of knockout of a negative regulator of NK activation (CISH) and CAR based antigen targeting can synergistically improve NK cell activation (Figures 22A-D). Trager further teaches CBLB is also a negative regulator of NK activation (¶ [0053]), and CBLB KO has a positive effect on NK cell cytotoxicity on REH cells (leukemia model cell line) proportionate to CISH KO NK cells (Figure 23A).
A skilled artisan would recognize that engineering NK cells to express both a CAR and a means to silence a negative regulator, such as CBLB siRNA as taught by Lametschwandtner, would likely improve NK cell responsiveness against target cells as implied by Trager. Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify an efficient method of engineering immune cells with both a CAR and siRNA via single vector as taught by Yu with a CBLB siRNA as taught by Lametschwandtner, because Trager teaches a dual strategy (i.e. CAR targeting and CBLB silencing) as synergistic for NK cell activation.
Conclusion
No claims are currently allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANNAH SUNSHINE whose telephone number is (571)270-7417. The examiner can normally be reached M-Th & Second Friday 8:30am-5pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached at (571) 272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/HANNAH SUNSHINE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
Prosecution Insights