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 .
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 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.
Priority
The instant application is a 371 filing of PCT/US2021/049315, filed 09/07/2021, and claims domestic benefit to US provisional applications 63/178,452, filed 04/22/2021, and 63/074,812, filed 09/04/2020.
Status of Claims/Application
Claims 1-202 are currently pending.
Election/Restrictions
Applicant’s election of the following species in the reply filed on 12/10/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
For the iCAR, applicant elected the following species:
scFv of the anti-HLA-hzBB7.2.1; the sequence of which is identified in the instant specification as SEQ ID NO: 287 (page 116, Table 4). The scFv is also identified as comprising heavy and light chain variable regions of SEQ ID NOs: 63 and 64, respectively, which are the VH and VL of Hz.BB7.2 VH1-69 (27,30,67)_A18.
hinge of LIR1;
transmembrane domain of LIR1;
inhibitory domain of LIR1;
VR428-SEQ ID NO: 259 from Table 11; VR428, SEQ ID NO: 259, is noted to comprise a LIR1 hinge of ILR1 52 aa hinge (SEQ ID NO: 89), as recited in instant claim 51; and a LIR1 inhibitory domain of SEQ ID NO: 143, as recited in instant claim 114.
For the aCAR, applicant elected the following species:
scFv of the anti-HER2-trastuzumab (SEQ ID NO: 172);
hinge and transmembrane domain of CD8;
costimulatory domain of 4-1BB; activation domain of CD3z; and
VR6 from Table 21; and
For the iCAR/aCAR construct,
VR428-SEQ ID NO: 278 from Table 1.
It is noted that in the response regarding the aCAR, applicant asserts that aCARs are the standard type of CAR and that the novelty and non-obviousness of the claims rest in the iCAR and its inclusion with an aCAR, not the aCAR itself. Applicant states that a search for the iCAR is sufficient but also provides an election of aCAR species for the purposes of search. This response, however, does not specifically point out any errors in the restriction requirement and the election is treated as an election without traverse and the election is maintained for search purposes. It is further noted that, upon the identification of allowable subject matter, non-elected species may be considered for rejoinder.
The election is made final.
Claims 6-10, 12-44, 46-50, 52-63, 65-67, 69-70, 72-113, 115-123, 127-162, 164, 168-169, 172-174, 176-178, and 182 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1-7, 11, 45, 51, 64, 68, 71, 114, 124-126, 163, 165-167, 170-171, 175, 179-181, and 183-202 are under examination in the instant office action to the degree that they read on the elected species.
The elected scFv, hzBB7.2.1, was found to be free of the prior art and the search was extended to include the additional species of scFv comprising the Vh and VL of antibody BB7.2, as recited in claim 7.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 06/26/2023 and 06/16/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
Figures 2A-E recite the sequence “(G4S)X3” multiple times without an appropriate SEQ ID NO either in the drawing or the description of the drawing in the specification.
Figure 25 recites the sequence “GGGG” without an appropriate SEQ ID NO either in the drawing or the description of the drawing in the specification.
The marked up specification of 03/03/2023 recites multiple sequences that are not identified with an appropriate SEQ ID NOs. It is noted that a SEQ ID NO is required when there are 4 or more “specifically defined” amino acids, for instance as recited in “Ser(Gly4Ser)n”. See the following paragraphs:
page 113, [00302];
pages 116-117, [00305]; and
pages 213-214, [0338];
Claim 71 recites “2xPD1(G4S)”. “G4S” comprises four specifically defined amino acids, but is not accompanied by an appropriate SEQ ID NO.
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Drawings
The drawings filed 03/03/2023 contain colored figures without an appropriate petition under 37 CFR 1.84(a)(2). Filing of an appropriate petition or replacement drawings in black and white/greyscale is required.
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 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).
The drawings are objected to because of the following informalities:
Figs. 11B-C and Fig 11F have annotations that are overlapping and cannot be read.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Multiple Dependent Claim Objection and Interpretation
Claims 4-6, 11, 45, 51, 64, 68, 71, 114, 124-126, 163, 165-167, 170-171, 175, 179-181, and 183-202 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from any other multiple dependent claim. See MPEP § 608.01(n). While MPEP 608.01(n) states that the claims are not required to be further treated on the merits, the following interpretations were made for the purposes of applying prior art in an effort towards compact prosecution (claim/dependency): 4/3; 5/1; 6/5; 45/1; 64/1; 71/1; 124/1; 125/124; 163/1; 166/1; 170/1; 175/1; 179/1; 180/179; 181/1; 183/1; 184/1; 185/1; 186;1; 187/1; 188/1; 190/1; 190/1; 191/1; 192/1; 194/188; 197/188; 198/1; 199/192; 200/192; and 201/188.
Claim Objections
Claim 2 recites the linker GGGGSGGGGSGGGGS twice, specifically recited as “(G4S)X3 linker (SEQ ID NO: 81)” and “(G4S)X3 (SEQ ID NO: 154)”. The sequences of SEQ ID NOs: 81 and 154 further support the claim to duplicate linkers as the sequences are identical. It is suggested that one of the redundant recitations be removed. Appropriate correction/clarification is required.
Claims 202 is objected to because of the following informality: the claim recites “Acute Myeloid Leukemia [LAML]”. The art recognized abbreviation for Acute Myeloid Leukemia is AML, not LAML, and, as such, it appears that “LAML” is a typo for “AML”. Appropriate correction/clarification 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.
Claims 1-6, 11, 45, 51, 64, 68, 71, 114, 124-126, 163, 165-167, 170-171, 175, 179-181, and 183-202 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 limitations “single chain variable fragment (scFv) component optionally in the VH-VL or VL-VH orientation” on lines 4-5 and 10-11. The optional orientations recited are narrower embodiments of the preceding scFv limitation. As such, the use of “optionally” in this instance renders the claim indefinite as it is unclear if the limitations that follow the term are required features of the claimed invention or exemplary embodiments. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 1 recites the broad recitation scFv, and the claim also recites VH-VL or VL-VH orientation, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Additionally, claim 1 recites “a linker that connects the iCAR portion in (i) and the aCAR portion in (ii)” in the last line of the claim. The claim, however, does not recite a (i) or (ii) portion that could be being referenced and, therefore, there is insufficient antecedent basis for these limitations in the claim.
Additionally, it is unclear how the claimed constructs can comprise monocistronic aCAR and iCAR constructs while also requiring that the iCAR and aCAR construct be connected by a linker as recited in the last line of the claim.
Appropriate correction is required.
Claims 2-6, 11, 45, 51, 64, 68, 71, 114, 124-126, 163, 165-167, 170-171, 175, 179-181, and 183-202 are rejected by virtue of their dependency on claim 1 as they do not resolve the ambiguity discussed above.
Claim 2 is drawn to the aCAR/iCAR constructs of claim 1, and recites “wherein the linker connecting the VH-VL or VL-VH in either orientation comprises one or more linker selected from the group consisting of…” There is insufficient antecedent basis for “the linker connecting the VH-VL or VL-VH in either orientation. While claim 1 recites an scFv and the orientations recited in the claim, claim 1 does not recite a linker that is used to connect the VH/VL.
Additionally, claim 1 recites VH-VL or VL-VH orientations twice, once regarding the iCAR scFv and again regarding the aCAR scFv. As such, it is unclear whether the iCAR or aCAR or if both are being limited by the linkers recited in claim 2 rendering the metes and bounds of the claim indefinite. See MPEP 2173.05(e) which states “ if two different levers are recited earlier in the claim, the recitation of "said lever" in the same or subsequent claim would be unclear where it is uncertain which of the two levers was intended. “
Claim 3 is rejected by virtue of its dependency on claim 2 as it does not resolve the ambiguity discussed above.
Appropriate correction is required.
Claims 5 and 6 recite that the iCAR scFv component is selected from the group(s) recited. The recited group(s), however, are not scFvs, but rather are applicant assigned names for antibodies, which are disclosed in the specification as comprising VH and VL regions. As such, it is unclear if the scFvs are required to have a specific sequence structure, or if the scFvs are only required to comprise the VH and VL regions of the disclosed antibodies. It is unclear, for example, if the orientations of the VH/VL regions is being limited and/or if a linker must be present to connect the VH/VL regions and, if so, what the linker must be. For instance, claim 5 recites that the scFv component can be VH1-69 (27,30,67)_A18; however, VH1-69 (27,30,67)_A18 is defined in the specification by a VH and VL domain and it is not readily apparent that VH1-69 (27,30,67)_A18 represents any specific scFv.
As the metes and bounds of the claims are unclear, the claims are indefinite.
Appropriate correction is required.
Claim 45 recites the limitation “a CD8 hinge (including a CD8a hinge)” in lines 3-4. The recitation of “including a CD8a hinge” in parentheticals renders the limitation indefinite as it is unclear if the CD8a hinge, which is a narrower embodiment of a CD8 hinge, is a required feature of the claimed invention or an exemplary embodiment.
Additionally, the claim recites “a PD-1 (47) hinge, a PD-1 (42) hinge, a PD-1 (36) hinge, a PD-1 (30) hinge, a PD-1 (26) hinge, and a PD-1 (20) hinge” in lines 6-7. The inclusion of the PD-1 hinge length in parentheticals renders the claim indefinite as it is unclear if the length is a limiting feature of the claimed invention or an exemplary embodiment.
Appropriate correction is required.
Claim 64 recites the limitation “a CD8 TM domain (including a CD8a TM domain)” in lines 3-4. The recitation of “including a CD8a TM domain” in parentheticals renders the limitation indefinite as it is unclear if the CD8a TM domain, which is a narrower embodiment of a CD8 TM domain, is a required feature of the claimed invention or an exemplary embodiment.
Appropriate correction is required.
Claim 68 recites the limitation that the iCAR TM domain comprises a “LIR1 TM domain (SEQ ID NO: 98)”. The inclusion of the SEQ ID NO in parentheticals renders the claim indefinite as it is unclear if the sequence is a required feature of the claim or if any LIR1 TM domain would meet the instant claim limitations.
Appropriate correction is required.
Claim 114 recites the limitation that the iCAR inhibitory domain component is a “LIR1 inhibitory domain (SEQ ID NO: 143)”. The inclusion of the SEQ ID NO in parentheticals renders the claim indefinite as it is unclear if the sequence is a required feature of the claim or if any LIR1 inhibitory domain would meet the instant claim limitations.
Appropriate correction is required.
Claim 163 is interpreted in the instant office action as being dependent on claim 1. The claim recites the limitation “wherein the hinge TM domain component”. There is insufficient antecedent basis for this limitation in the claim. Claim 1 recites an iCAR comprising a hinge component and a TM component and an aCAR comprising a hinge component. The claim does not recite a hinge TM domain compnent. It is unclear if the recitation of “the hinge TM domain component” is in reference to the iCAR hinge component and TM component taken together or if the limitation is in reference to the hinge component of the aCAR. This is particularly the case in view of the species election in which the hinge and transmembrane domain of the aCAR was elected as being from CD8.
Additionally, the claim recites the limitation “the hinge TM domain component is selected from the group consisting of a CD28 hinge and a CD8 hinge (including a CD8a hinge domain)” in lines 3-4. It is unclear if these limitations are attempting to limit both the hinge and TM domain of one of the CARs or only the hinge. Furthermore, the recitation of “including a CD8a hinge” in parentheticals renders the limitation indefinite as it is unclear if the CD8a hinge, which is a narrower embodiment of a CD8 hinge, is a required feature of the claimed invention or an exemplary embodiment.
Appropriate correction is required.
Claim 165 depends on claim 163 and recites the limitation “the hinge TM domain component is a CD8 alpha hinge domain (SEQ ID NO: 84).” It is unclear if these limitations are attempting to limit both the hinge and TM domain of one of the CARs or only the hinge. Furthermore, the inclusion of the SEQ ID NO in parentheticals renders the claim indefinite as it is unclear if the sequence is a required feature of the claim or if any CD8 alpha hinge domain would meet the instant claim limitations.
Appropriate correction is required.
Claim 167 recites the limitation “CD137 (4-1BB) co-stimulatory domain (SEQ ID NO: 233).” The inclusion of the SEQ ID NO in parentheticals renders the claim indefinite as it is unclear if the sequence is a required feature of the claim or if any CD137 (4-1BB) co-stimulatory domain would meet the instant claim limitations.
Appropriate correction is required.
Claim 170 recites the limitation “the ITAM”. There is insufficient antecedent basis for this limitation in the claim. The claim is interpreted in the instant office action as depending on claim 1, which does not recite an ITAM that could be being referenced rendering the metes and bounds of the claim indefinite.
Appropriate correction is required.
Claim 171 recites the limitation “CD3 zeta domain (SEQ ID NO: 236).” The inclusion of the SEQ ID NO in parentheticals renders the claim indefinite as it is unclear if the sequence is a required feature of the claim or if any CD3 zeta domain would meet the instant claim limitations.
Appropriate correction is required.
Claim 175 recites the limitations “T2A (SEQ ID NO: 155), F2A (SEQ ID NO: 156), P2A (SEQ ID NO: 157), E2A (SEQ ID NO: 158), and an IRES sequence (SEQ ID NO: 159 or 160).” The inclusion of the SEQ ID NOs in parentheticals renders the claim indefinite as it is unclear if the sequences are a required feature of the claim or if any T2A, F2A, P2A, E2A, or IRES linker would meet the instant claim limitations.
Appropriate correction is required.
Claims 182-185 and 187-190 all reference Tables in the specification. MPEP 2173.05(s) states “Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993)”.
Appropriate correction is required.
Claim 193 recites “the vector according to claim 188”. There is insufficient antecedent basis for this limitation in the claim. Claim 188 recites a construct or a portion thereof as described in any one of Tables 1 to 22. The claim does not recite a vector. Additionally, the tables referenced by claim 188 comprise various iCAR components, not vectors.
Appropriate correction is required.
Claim 194 currently recites “the nucleic acid or vector according to claim 187 to 189”. In the instant office action the claim is being interpreted as depending on claim 188, as it is within the scope of the existing claim. The recitation of “the nucleic acid or vector according to claim 187 to 189”, or in the case of the instant interpretation, claim 188, lacks sufficient antecedent basis. In the instant office action, claim 188 is interpreted as depending on claim 1 and, under this interpretation, is drawn to the bicistronic iCAR/aCAR construct or monocistronic aCAR and iCAR constructs for co-transduction according to claim 1. The claim does not recite a nucleic acid and vector that could be being referenced.
Appropriate correction is required.
Claim 195 recites “the nucleic acid or vector according to claim 190”. There is insufficient antecedent basis for this limitation in the claim. Claim 190 is drawn to the bicistronic iCAR/aCAR construct or monocistronic aCAR and iCAR constructs for co-transduction according to claim 1. The claim does not recite a nucleic acid or vector.
Additionally, the claim is dependent on claim 190 and recites the limitation “the signal peptide”. There is insufficient antecedent basis for this limitation in the claim as claim 190 does not recite a signal peptide.
Additionally, the claim recites “CD8 alpha signal peptide (SEQ ID NO: 161), a GM-CSF signal peptide (SEQ ID NO: 162), or a mIgK signal peptide (SEQ ID NO: 306).” The inclusion of the SEQ ID NOs in parentheticals renders the claim indefinite as it is unclear if the sequences are a required feature of the claim or if any CD8 alpha, GM-CSF, or mIgK signal peptide would meet the instant claim limitations.
Appropriate correction is required.
Claim 197 recites a safe effector cell comprising a vector or vector composition according to claims 188 or 189. In the instant office action, the claim is interpreted as being dependent on claim 188. Under both the recited dependency and the interpretation in the instant office action, there is insufficient antecedent basis for the limitations “vector or vector composition” in the claim. Claims 188 and 189 recite constructs or a portion thereof as described in any one of the recited tables. The claims do not recite a vector or a vector composition.
Appropriate correction is required.
Claims 199 and 200 recite methods for treating a patient having cancer comprising administering “a safe effector immune cell according to any one of claims 192 to 194”. In the instant office action, the claims are interpreted as being dependent on claim 192, as it is within with the current claim dependency; however, under this interpretation, there is insufficient antecedent basis for “a safe effector immune cell according to claim 192”. Claim 192 recites a vector, and does not recite a safe effector immune cell that could be being referenced.
Appropriate correction is required.
Claim 201 recites a method for treating a patient having cancer comprising administering “a safe effector immune cell according to any one of claims 188 to 190”. In the instant office action, the claims are interpreted as being dependent on claim 188, as it is within with the current claim dependency; however, under this interpretation, there is insufficient antecedent basis for “a safe effector immune cell according to claim 188”. Claim 188 does not recite a safe effector immune cell that could be being referenced.
Appropriate correction is required.
Claim 202 depends on claim 193 and recites “the cancer”. There is insufficient antecedent basis for this limitation in the claim. Claim 193 is drawn to a vector and does not recite “a cancer” that could be being referenced.
Appropriate correction is required.
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 11 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.
Claim 11 depends on claim 6 and recites that the iCAR scFv comprises the Vh and Vl from Hz.BB7.2 VH1-69 (27,30,67)_A18, which are SEQ ID NOs: 63 and 64, or the vhCDRs 1-3 and vlCDRs 1-3, thereof. Claim 6, however, requires that the iCAR scFv component be BB7.2. The instant specification, page 76, defines the BB7.2 scFv as being SEQ ID NO: 167, which comprises the VH and VL of BB7.2 and a linker joining the variable regions. Additionally, the disclosed BB7.2 CAR does not comprise the Vh and Vl of Hz.BB7.2 VH1-69 (27,30,67)_A18, which is claimed in instant claim 11. Therefore, claim 11 does not include all of the limitations of the claim upon which it depends and also does not further limit the claim upon which it depends.
Furthermore, claim 5, on which claim 6 depends, recites that the iCAR scFv component is selected from a group which includes Hz.BB7.2 VH1-69 (27,30,67)_A18. As Hz.BB7.2 VH1-69 (27,30,67)_A18 is defined by the sequences recited in claim 11 the claim also does not further limit the recitations of claim 5.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 45, 64, 71, 124, 163, 166, and 170 are rejected under 35 U.S.C. 103 as being unpatentable over US 10,172,885 B2 (Pule, M., et al) 08 JAN 2019.
US’885 teaches a cell that co-expresses a first chimeric antigen receptor (CAR) and a second CAR at the cell surface, each CAR comprising: (i) an antigen-binding domain; (ii) a spacer; (iii) a transmembrane domain; and (iv) an endodomain; wherein the antigen binding domains of the first and second CAR bind to different antigens, and wherein one of the first or second CAR is an activating CAR comprising an activating domain and the other CAR is an inhibitory CAR comprising a ligation-off inhibitory endodomain (abstract).
US’885 teaches bicistronic activating and inhibitory CAR constructs, for instance, Fig. 12, which provides versions of cassettes used to generate “AND NOT” gates. Fig. 12 shows a construct through which activating and inhibiting CARs were co-expressed using a FMD-2A sequence. The construct comprises an activating CAR comprising Signal 1, which is a signal peptide derived from IgG1; an scFv that recognizes CD19; STK which is the stalk of human 8; a CD28 transmembrane domain; and CD3Z which is the CD3 zeta endodomain. The inhibitory CAR comprises Signal 2, which is a signal peptide derived from CD8; an scFv that recognizes CD33; muSTK, which is a mouse CD8 stalk; and LAIR1, which comprises the transmembrane and endodomain of LAIR1. The CAR constructs are connected together by a 2A linker, specifically a FMD-2A sequence (col. 4, lines 4-27; Fig. 12). The second construct from Fig 12 of US’885 is shown below and has been annotated to clearly show the domains within the construct:
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US’885 further studied the functional activity the LAIR1 based AND NOT gates against CD19 positive, CD33 positive, and CD19, CD33 double-positive targets and, in Fig. 23A provides the following results:
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As shown, the effector cell is not activated in the presence of both CD19 and CD33 or CD33 alone, but is activated in the presence of CD19 alone.
US’885 teaches that the second signal “vetos” activation by bringing an inhibitory signal into the immunological synapse. US’885 teaches that T cells were transduced with the gates and challenged with the targets confirming that the AND NOT gates were functional (col. 51-52, Example 7). US’885 also teaches a nucleic acid that encodes the bicistronic construct (SEQ ID NO: 39; col. 44, line 19 – col. 45, line 45), the amino acid translation of which shows that the linker between the scFv regions is (G4S)X4, which comprises the (G4S)X3 and G4S linkers of claim 2. US’885 further teaches that CARs were expressed in a bicistronic retroviral vector (col. 66, lines 56-57).
US’885 also teaches that the transmembrane domain can be any protein structure that is thermodynamically stable in the membrane. This is typically an alpha helix comprising of several hydrophobic residues. The transmembrane domain of any transmembrane protein can be used to supply the transmembrane portion, for instance, the transmembrane domain may be derived from CD28, which provides good receptor stability (col. 27, lines 1-16). US’885 also teaches alternative antigens that can be used as the target antigen of the aCAR including ErbB2 (col. 21, lines 30-49, Table 4), which is HER2.
US’885 further teaches that the nucleic acid may produce a polypeptide that comprises the two CAR molecules joined by a cleavage site. The cleavage site may be self-cleaving, such that when the polypeptide is produced, it is immediately cleaved into the first and second CARs without the need for any external cleavage activity. Various self-cleaving site are known, including the food-and-mouth disease virus (FMDV) 2a self-cleaving peptide. The co-expressing sequence may also be an internal ribosome entry sequence (IRES) (col. 33, line 66 – col. 34, line 15).
In the iCAR/aCAR constructs exemplified by US’885, the aCAR does not include a co-stimulatory domain as required by the instant claims. The further inclusion of a co-stimulatory domain, however, would have been obvious in view of the further teachings of US’885.
Specifically, US’885 teaches that the endodomain is the signal-transmission portion of the CAR. The most commonly used component is that of CD3-zeta, which contains 3 ITAMs. This transmits an activation signal to the T cell after antigen is bound. CD3-zeta may not provide a fully competent activation signal and additional co-stimulatory signaling may be needed. For example, chimeric CD28 and OX40 can be used with CD3-zeta to transmit a proliferative/survival signal, or all three can be fused together. US’885 teaches that the CAR with an activating endodomain may comprise a CD3-zeta endodomain alone, the CD3-zeta endodomain with that of either CD28 or OX40, or the CD28 endodomain and the OX40 and the CD3-zeta endodomains (col. 27, lines 16-32).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the exemplified iCAR/aCAR constructs taught by US’885 to further include a CD28 and/or OX40 co-stimulatory domain along with the CD3-zeta signaling domain. An ordinarily skilled artisan would have been motivated to further include the co-stimulatory domain in order to enhance the activation signal providing proliferative/survival signals. An ordinarily skilled artisan would have had a reasonable expectation of success as US’885 teaches that the co-stimulatory domains can be added to the activating CAR.
Claims 1, 3-4, 45, 64, 71, 124, 163, 166, 170, 191-192, 196, and 198-200 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/061012 A1 (Gross, G., et al) 05 Apr 2018 as evidenced by Tan, S., et al (2017) An unexpected N-terminal loop in PD-1 dominates binding by nivolumab Nature Communications 8(14369); 1-10.
WO’012 teaches that off-tumor reactivity occurs when the target antigen of a CAR-redirected killer cell is shared with normal tissue. If this normal tissue expresses another surface antigen not present on the tumor, then co-expressing in the gene modified cells an additional CAR targeting this non-shared antigen, which harbors an inhibitory signaling moiety, can prevent cell activation by the normal tissue (page 4, lines 11-15). Instead of an activating domain, such as FcRγ or CD3ζ, an iCAR possesses a signaling domain derived from an inhibitory receptor which can antagonize T cell activation. If the normal tissue, which shares the candidate activating CAR antigen with the tumor expresses another surface antigen not shared with the tumor, an iCAR expressed by the same T cell that targets this non-shared antigen can protect the normal tissue (page 4, lines 16-21, Fig. 1).
WO’012 teaches a nucleic acid molecule comprising a nucleotide sequence encoding an inhibitory chimeric antigen receptor (iCAR) capable of preventing or attenuating undesired activation of an immune effector cell, where the iCAR comprises an extracellular domain that specifically binds to a single allelic variant of a polymorphic cell surface epitope absent from mammalian tumor cells due to loss of heterozygosity (LOH) but present at least on all cells of related mammalian normal tissue; and an intracellular domain comprising at least one signal transduction element that inhibits an effector immune cell (page 68, claim 1). WO’012 further teaches that the extracellular domain of the iCAR is fused through a flexible hinge and transmembrane canonic motif to the intracellular domain (page 69, claim 8). WO’012 teaches that the extracellular domain comprises a scFv (page 68, claim 3) and that the polymorphic cell surface epitope is of a housekeeping gene product, such as an HLA type I, preferably an HLA-A, HLA-B, or HLA-C (page 68, claim 2). WO’012 further teaches that the signal transduction element that inhibits an effector immune cell is homologous to a single transduction element of an immune cell checkpoint protein, including PD1; 2B4; CD160; CEACAM1; KIRs, such as KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR2DL5A, KIR3DL1, KIR3DL2, KIR3DL3, LIR1, LIR2, LIR3, LIR5, and LIR8; LAG3; TIM3; VISTA, and TIGIT (pages 68-69, claim 7).
WO’012 further teaches a vector comprising the nucleic acid encoding the iCAR, and teaches that the vector further comprises a nucleic acid molecule sequence encoding an aCAR comprising an extracellular domain specifically binding a non-polymorphic cell surface epitope of a tumor associated antigen and an intracellular domain comprising at least one signal transduction element that activates and/or co-stimulates an effector immune cell (page 6, claims 9-10). WO’012 teaches that the extracellular domain of the aCAR specifically binds to antigens such as those disclosed in Table 1 (page 69, claim 13), including HER2, which is expressed in brain cancer, CNS cancer, glioblastoma, head and neck cancer, and solid tumors (page 55; Last row). WO’012 further teaches that the aCAR extracellular binding domain is an scFv (page 1, line 23 – page 2, line 1; page 24, lines 14-21).
WO’012 further teaches that the signal transduction element of the aCAR is homologous to an immunoreceptor tyrosine based activation motif (ITAM), for example of CD3ζ. WO’012 also teaches co-stimulatory signal transduction elements for inclusion in the aCAR including CD27, CD28, ICOS, CD137 (4-1BB) or CD134 (OX40) (page 69, claim 13). WO’012 further teaches embodiments including 2nd generation CARs comprising a co-stimulatory and intracellular signaling domain as well as 3rd generation CARs that comprise two co-stimulatory domains and an intracellular signaling domain. WO’012 further teaches examples in which the aCAR comprises an scFv as the extracellular domain as well as a CD8 or CD28 hinge and a CD28 transmembrane domain (page 50, lines 5-9).
WO’012 further teaches that, in the vector, the nucleotide sequence comprises an internal ribosome entry site (IRES) between the nucleotide sequence encoding for the aCAR and the nucleotide sequence encoding for the iCAR (page 70, claim 14). WO’012 alternatively teaches viral self-cleaving 2A peptides between the nucleotide sequences including T2A, F2A, E2A, and P2A (page 70, claims 16-17), which is indicative of a bicistronic construct. WO’012 further teaches that permanent dominance of the inhibitory signal over the activating one is mandatory and; therefore, it is crucial to ensure that the aCAR is not expressed in the absence of its iCAR safeguard. This may be implemented through tandem assembly of the iCAR-aCAR gene pairs as single-chain products or viva a suitable bicistronic modality based, for example on an IRES or a self-cleaving 2A peptide (page 22, lines 3-11).
WO’012 further teaches methods of preparing safe effector immune cells comprising transfecting an effector immune cell with a nucleic acid molecule comprising a nucleotide sequence encoding an iCAR and aCAR, or transducing an effector immune cell with a disclosed vector. WO’012 also teaches safe effector immune cells obtained by the method disclosed and teaches that the effector immune cell expresses the iCAR and aCAR (page 7, lines 10-25).
WO’012 further teaches a method of treating cancer in a patient having a tumor characterized by loss of heterozygosity (LOH) comprising administering to the cancer patient at least one population of safe redirected immune effector cells (page 30, line 24 – page 31, line 9). WO’012 further teaches that LOH results in absence of polymorphic cell surface epitopes on the tumor cells (page 6, lines 10-17). WO’012 further teaches that LOH is a genomic event resulting in a total loss of a specific variant from the tumor with a very rare probably of gaining back the lost allele (page 14, lines 3-14).
WO’012 further teaches that the cancer is selected from Acute Myeloid Leukemia [AML], Adrenocortical carcinoma [ACC], Bladder Urothelial Carcinoma [BLCA], Brain Lower Grade Glioma [LG(i], Breast invasive carcinoma [BRCA], Cervical squamous cell carcinoma and endocervical adenocarcinoma [CESC], Cholangiocarcinoma [CHOL], Colon adenocarcinoma [COAD], Esophageal carcinoma [ESCA], Glioblastoma multiforme [GBM], Head and Neck squamous cell carcinoma [HNSC], Kidney Chromophobe [KICH], Kidney renal clear cell carcinoma [KIRC], Kidney renal papillary cell carcinoma [KIRP], Liver hepatocellular, carcinoma [LIHC], Lung adenocarcinoma [LUAD], Lung squamous cell carcinoma [LUSC], Lymphoid Neoplasm Diffuse Large B-cell Lymphoma [DLBC], Mesothelioma [MESO], Ovarian serous cystadenocarcinoma [OV], Pancreatic adenocarcinoma [PAAD], Pheochromocytoma and Paraganglioma [PCPG], Prostate adenocarcinoma [PRAD], Rectum adenocarcinoma [READ], Sarcoma [SARC], Skin Cutaneous Melanoma [SKCM], Stomach adenocarcinoma [STAD], Testicular Germ Cell Tumors [TGCT], Thymoma [THYJVI], Thyroid carcinoma [THCA], Uterine Carcinosarcoma [UCS], Uterine Corpus Endometrial Carcinoma [UCEC], and Uveal Melanoma [UVM] (page 32, line 25 – page 33, line 8).
WO’012 provides an example CAR T construction which will inhibit the on-target off-tumor effect of CAR T cell therapy. The constructs include an inhibitory CAR directed at HLA-type I sequence, for example HLA-A2, and an activating CAR directed at a tumor antigen, for example CD19 (page 49, line 19 – page 50, line 16). In the iCAR construct, the transmembrane and intracellular domains of PD-1, specifically amino acids 145-288, or CTLA4, specifically amino acids 161-233, are fused downstream of a HLA-A2 scFv. WO’012 further teaches HLA-A2 antibodies, including BB7.2 (page 49, line 19 – page 50, line 16; page 46, table of Allele-specific anti-HLA antibodies). It is noted that, in this example, at least the PD-1 region disclosed by WO’012 includes the PD-1 stalk, or hinge, as evidenced by Tan, Fig. 1a, which demonstrates that the stalk, transmembrane domain, and cytoplasmic domain of PD-1 is from amino acid 145-288 (Tan, page 3, Fig. 1a)
The aCAR construct comprises a CD19 scFv in a 2nd generation CAR comprising a CD8 or CD28 hinge, CD28 transmembrane domain, CD28 or 41BB co-stimulatory domain and CD3ζ; or a 3rd generation CAR comprising a CD8 or CD28 hinge, a CD28 transmembrane domain, CD28 and 41BB co-stimulatory domains, and CD3ζ. WO’012 teaches that both the aCAR and iCAR sequences will be cloned into retrovirus or lentivirus transfer vectors and used for viral particle producing using appropriate packaging cells, for example HEK-293T. WO’012 further teaches that activated T cells derived from donors will be transduced with the aCAR and iCAR (page 49, line 19 – page 50, line 16).
While WO’012 does not does not exemplify an iCAR/aCAR bicistronic construct as claimed, WO’012 teaches iCAR and aCAR bicistronic constructs and teaches each element of the instantly claimed invention. As such, it would have been obvious to modify the teachings of WO’012 to arrive at the instantly claimed bicistronic iCAR/aCAR with a reasonable expectation of success.
Claims 2-3, 5-7, 11, 165, 167, 171, 181, 188, 190, 193, 197, and 201-202 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/061012 A1 (Gross, G., et al) 05 Apr 2018 as applied to claims 1, 163, 166, and 170 above, and in further view of WO 2019/056099 A1 (Levings, M., et al) 28 Mar 2019.
WO’012 teaches the bicistronic iCAR/aCAR construct of claims 1, 163, 166, and 170 as discussed in detail above.
As discussed above, WO’012 teaches that the iCAR is directed at an HLA-type I sequence, including HLA-A2 (page 49, lines 23-28) and teaches that the HLA-A2 scFv can be cloned and constructed from hybridomas expressing antibodies including BB7.2 (page 50, lines 3-4; page 46, Allele-specific anti-HLA antibodies table). WO’012 also teaches that the aCAR comprises a aCD8 hinge, the co-stimulatory domain of 4-1BB, and an endodomain of CD3 zeta.
WO’012, however, does not disclose that the linker connecting the VH-VL comprises one or more of those recited in claim 2, that the sequences of the HLA-A2 scFv, VH/VL, or CDRs as recited in instant claims 5-7 and 11, that the CD8 hinge comprises SEQ ID NO: 84, as recited in instant claim 165, that the 4-1BB costimulatory domain comprises SEQ ID NO: 233, as recited in instant claim 167, that the CD3 zeta domain comprises instant SEQ ID NO: 236 as recited in instant claim 171, or that the construct further comprises a shRNA as recited in instant claim 181.
WO’099 teaches humanized anti-HLA-A2 antibodies and teaches that the antibodies are capable of constituting an antigen binding domain of a chimeric antigen receptor where the CAR is capable of being expressed in a human cell, such that the CAR specifically binds to HLA-A2 (abstract).
WO’099 teaches the antibody BB7.2, which refers to a murine hybridoma identified as ATCC deposit HB-82. The BB7.2 hybridoma cell secretes a murine monoclonal antibody of IgG2b kappa isotope, which had been previously characterized. The amino acid sequences of the six complementarity determining regions (CDRs) of the monoclonal antibody secreted by BB7.2 are provided as follows:
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The CDRs disclosed by WO’099 are the same as those from instant SEQ ID NOs: 63 and 64 (antibody Hz.BB7.2 VH1-69(27,30,67), according to the instant specification which shows the CDRs of the variable regions as follows, and; therefore, meet the limitation of instant claim 11:
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WO’099 further teaches that the BB7.2 antibody has a VH and VL of SEQ ID NOs: 191 and 192, respectively. WO’099 teaches that a BB7.2 antibody may be a whole antibody or a fragment thereof having the VH and VL of the monoclonal antibody secreted by BB7.2, such as an scFv having the VH and VL of the monoclonal antibody secreted by BB7.2 (page 24).
The VH and VL of SEQ ID NOs: 191 and 192, disclosed by WO’099 as those of BB7.2, are identical to the instantly claimed BB7.2 VH and VL sequences of SEQ ID NO: 38 and 37, respectively, as shown in the ABSS alignments below:
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WO’099 teaches that single chain Fv, also abbreviated as “scFv” is an antibody fragment that comprises the VH and VL antibody domains connected into a single polypeptide chain. The scFv polypeptide may further comprise a polypeptide linker between the VH and VL domains, which enables the scFv to form the desired structure for antigen binding. The scFv may have the VL and VH variable regions in either order with respect to the N-terminal and C-terminal ends of the polypeptide. The scFv may comprise VL-linker-VH or may comprise VH-linker-VL (page 28, paragraph 2).
WO’099 further teaches that the term “flexible polypeptide linker” or “linker” in the context of an scFv refers to a peptide linker that consists of amino acids such as glycine and/or serine residues used alone or in combination, to link the VH and VL regions together. In one embodiment, the flexible polypeptide linker comprises the amino acid sequence (Gly-Gly-Gly-Ser)n, where n is 1-10. WO’099 also teaches linkers including (Gly4Ser)3 (page 30, paragraph 3).
The use of the (Gly4Ser)3 linker with the VH and VL disclosed by WO’099 for BB7.2 provides an scFv that is identical to that of instant SEQ ID NO: 167, which is the disclosed BB7.2 scFv component, meeting the limitations of claims 5 and 6, as shown in the alignment below:
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WO’099 teaches that the CARs can comprise a hinge region, including the stalk region of CD8α (page 0, paragraph 3). The CAR may also include a transmembrane domain including the transmembrane domain of CD8 or CD28 (page 9, paragraph 4). The CAR also includes an intracellular signaling domain including a functional signaling domain of a protein including CD3 zeta as well as a costimulatory domain including a protein selected from CD28 and 4-1BB (page 10, paragraph 1).
WO’099 further teaches a CD8α hinge domain of SEQ ID NO: 219 (page 197), that is identical to instant SEQ ID NO: 84, as shown in the ABSS alignment below:
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WO’099 further teaches a 4-1BB co-stimulatory domain of SEQ ID NO: 216 (page 196), that is identical to instant SEQ ID NO: 233, as shown in the ABSS alignment below:
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WO’099 further teaches a CD3 zeta intracellular signaling domain of SEQ ID NO: 118 (page 191, CD3z), which is identical to instant SEQ ID NO: 236, as shown in the alignment below:
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WO’099 further teaches that the genetically modified cells can be engineered such that they do not express a functional HLA on its surface. For example, an immune cell described can be engineered such that the cell surface expression of HLA, including HLA class 1 and/or HLA class II, or non-classical HLA molecules is downregulated. In another embodiment, the T cell can lack a functional TCR and a functional HLA. Modified immune cells (such as for example, modified T or Treg cells) that lack expression of functional TCR and/or HLA can be obtained by any suitable means, including a knock out or knockdown of one or more subunits of TCR and/or HLA. For example, the immune cell can include a knock down of TCR and/or HLA using shRNA (page 154, paragraphs 3-5).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the bicistronic iCAR/aCAR construct taught by WO’012 by using the flexible linkers, including (GGGS) and (G4S)X3, disclosed by WO’099 for linking the VH/VL of the scFvs, to use the amino acid sequences disclosed by WO’099 for the BB7.2 antibody in the scFv of the iCAR, as well as the sequences disclosed by WO’099 for the CD8a hinge, 4-1BB costimulatory domain, and the CD3z domains in the aCAR, and to further include a shRNA in the construct, for instance, a shRNA that targets the TCR or HLA of the immune cell, as taught by WO’099.
It would have been obvious to use the linkers disclosed by WO’099 for the scFvs as WO’099 teaches the use of the linkers in the formation of scFvs for use in CAR constructs. An ordinarily skilled artisan would have had a reasonable expectation of success as both WO’012 and WO’099 teach scFvs for use in CAR constructs.
It would have also been obvious to use the amino acid sequences of BB7.2 disclosed by WO’099 as WO’012 teaches that the iCAR can target HLA-A2 and can comprise an scFv from an antibody including BB7.2. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
It would have been obvious to use the amino acid sequences of the CD8a hinge, 4-1BB costimulatory, and the CD3z domains disclosed by WO’099 in the aCAR as WO’012 teaches that the aCAR can comprise a CD8 hinge, a 4-1BB costimulatory domain, and a CD3z domain. Thus an ordinarily skilled artisan would have had a reasonable expectation of success.
An ordinarily skilled artisan would have been motivated to further include a shRNA in order to downregulate or knockout the TCR and/or HLA in the immune cells. An ordinarily skilled artisan would have had a reasonable expectation of success as both WO’012 and WO’099 are both teaching modified effector cells expressing CARs, including T cells.
Regarding claims 188 and 190, using the BB7.2 scFv disclosed by WO’099 in the iCAR construct of WO’012 meets the instant claim limitations as both the Vh and Vl as well as the BB7.2 scFv are constructs that are disclosed in instant Tables 2 and 4. As the claims only require that the iCAR comprise one of the constructs disclosed in one of the tables recited, the inclusion of the BB7.2 Vh and Vl or scFv in the iCAR meets the instant claim limitations.
Claims 51 and 114 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/061012 A1 (Gross, G., et al) 05 Apr 2018 as applied to claims 1, 45, and 64 above, and in further view of NCBI reference sequence: NM_006669.6, Homo sapiens leukocyte immunoglobulin like receptor B1 (LILRB1), transcript variant 1, mRNA, PRI 31-May-2020.
WO’012 teaches the bicistronic iCAR/aCAR construct of claims 1, 45, and 64 as discussed above,
As discussed above, WO’012 teaches that the iCAR comprises an intracellular domain comprising at least one signal transduction element which can include the signal transduction element of ILR-1 (page 68, claims 1, 6-7). WO’012 also teaches that the iCAR can comprise a flexible hinge and transmembrane canonic motif connecting the extracellular domain to the intracellular signaling domain (page 69, claim 8). WO’012 also discloses example constructs where the hinge, transmembrane, and intracellular domains of PD-1 are fused downstream to the iCAR HLA-A2 scFv (page 49, lines 29-31).
WO’012, however, does not disclose the sequence of the ILR-1 domains that are used in the iCAR. Specifically, WO’012 does not disclose that the stalk/hinge comprises SEQ ID NO: 89, as recited in claim 51, or that the LIR1 inhibitory domain comprises SEQ ID NO: 143 as recited in instant claim 114.
NM_006669.6 provides the gene and amino acid sequence of LILRB1, synonymous with LIR-1 and LIR1 (page 3, gene). NM_006669.6 teaches that the gene is a member of the leukocyte immunoglobulin-like receptor (LIR) family. The encoded protein belons to the subfamily B class of LIR receptors which contain two or our extracellular immunoglobulin domains, a transmembrane domain, and two or four cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs) (page 2; Summary).
NM_006669.6 provides the amino acid translation of the ILR1 gene on page 4.
The ILR1 amino acid sequence disclosed by NM_006669.6 comprises a stalk/hinge domain that is identical to instant SEQ ID NO: 89, as shown in the ABSS alignment below:
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The ILR1 sequence also comprises an intracellular signaling domain that is identical to instant SEQ ID NO: 143, as shown in the ABSS alignment below:
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It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the iCAR in the bicistronic construct disclosed by WO’012 by using the amino acid sequences of ILR1 disclosed by NM_006669.6 for the ILR1 components of the iCAR. It would have been obvious to use the sequences disclosed by NM_006669.6 because the sequence is the known amino acid sequence of human ILR1 and WO’012 teaches that the iCAR domains can be derived from ILR1. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Claims 125-126, and 189 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/061012 A1 (Gross, G., et al) 05 Apr 2018 as applied to claims 1 and 124 above, and in further view of WO 2014/018572 A2 (Dixit, S.B., et al) 03 Jan 2014.
WO’012 teaches the bicistronic iCAR/aCAR construct of claim 1 as discussed in detail above.
As discussed above, WO’012 teaches that the extracellular domain of the aCAR binds to an antigen including ErbB2, also known as HER2 (page 55, table 1; page 33, lines 12-19) and that the extracellular domain comprises an scFv (page 24, lines 14-21).
WO’012; however, does not disclose that the scFv comprises the Vh and Vl of trastuzumab or that the aCAR scFv is SEQ ID NO: 172.
WO’572 teaches immunoglobulin constructs comprising single chain Fv (scFv) polypeptides (abstract) including constructs that bind to an antigen expressed by cancer cells, such as HER2 (pages 5-6, [0015]). WO’572 teaches an scFab of SEQ ID NO: 2, referenced as variant 656, which comprises a heavy and light chain variable region based on 4D5 in an scFv (page 55, [00203]). The sequence disclosed comprises an scFv that is identical to instantly claimed SEQ ID NO: 172 as shown in the ABSS alignment below:
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The sequence above also comprises the VH and VL of trastuzumab (SEQ ID NOs: 170 and 171) as shown in the alignments below:
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It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the aCAR taught by WO’012 to use the anti-HER2 scFv disclosed by WO’572 as the scFv targeting HER2 in the aCAR. It would have been obvious to use the anti-HER2 scFv as WO’572 demonstrates that it was a known ant-HER2 scFv for use in immunoglobulin constructs. An ordinarily skilled artisan would have had a reasonable expectation of success as WO’012 teaches that the aCAR comprises an scFv extracellular binding region that bind HER2 and WO’572 teaches constructs comprising scFvs that bind HER2.
Regarding claim 189, the VH and VL of trastuzumab and the scFv disclosed by the combination of WO’012 and WO’572 are constructs that are disclosed in instant Table 15. As the claims only require that the aCAR comprise one of the constructs disclosed in the tables recited, the inclusion of these VH/VL and scFv sequences meets the instant claim limitations.
Claim 175 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/061012 A1 (Gross, G., et al) 05 Apr 2018 as applied to claims 1 and 124 above, and in further view of GenBank: AB673344.1 Gene-trapping transposon vector pUPATrap-TMtt-14DNA, compete sequence SYN 08-SEP-2012.
WO’012 teaches the bicistronic iCAR/aCAR construct of claim 1 as discussed in detail above.
As discussed above, WO’012 teaches that the nucleotide sequence of the vector comprises an internal ribosome entry site (IRES) between the nucleotide sequence encoding for the aCAR and the nucleotide sequence encoding for the iCAR (page 26, lines 20-25).
WO’012, however, does not disclose the nucleic acid sequence of the IRES or that it comprises SEQ ID NOs 159 or 160.
GenBank: AB673344.1 teaches a sequence for EMCV-IRES (page 1), which is identical to instant SEQ ID NO: 159, as shown in the ABSS alignment below:
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It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the bicistronic construct taught by WO’012 by using the EMCV-IRES sequence disclosed by GenBank: AB673344.1 as the IRES sequence used between the nucleic acid sequences encoding for the iCAR and aCAR. It would have been obvious to use the sequence disclosed by GenBank: AB673344.1 as the sequence is an IRES sequence for use in vectors that was known in the prior art. An ordinarily skilled artisan would have had a reasonable expectation of success as US’012 teaches that the vector encoding the bicistronic CAR construct comprises an IRES sequence.
Claims 194-195 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/061012 A1 (Gross, G., et al) 05 Apr 2018 in view of WO 2019/056099 A1 (Levings, M., et al) 28 Mar 2019 as applied to claim 188 and 190 above, and in further view of AU 2018/227583 B2 (Suri, V., et al) 07 Sept 2018.
The combination of WO’012 and WO’099 teach the bicistronic iCAR/aCAR construct of claim 188 as discussed in detail above.
The combination of applied references, however, does not disclose that the nucleic acids comprise a signal peptide upstream of the iCAR and/or aCAR portions or that the signal peptide is one of those recited in instant claim 195
AU’583 teaches CARs comprising extracellular targeting domains, transmembrane domains, intracellular signaling domains, and co-stimulatory domains (page 4, [0016]). AU’583 further teaches signal peptides for use in CAR construction. AU’583 teaches that a signal sequence is a short, 5-30 amino acids long, peptide present at the N-terminus of the majority of newly synthesized proteins that are destined towards a particular location. Signal sequences derived from human proteins can be incorporated as a regulatory module of the effector molecule to direct the effector molecule to a particular extracellular location (page 127, [00271]). AU’583 teaches that the signal sequence directs the payload of interest to the surface membrane of the target cell and that expression of the payload on the surface of the target cell may be useful to limit the diffusion of the payload to non-target in vivo environments. AU’583 further teaches that signal sequences may be selected based on their compatibility with the secretory pathway of the cell type of interest so that the payload is presented on the surface of a T cell. Au’586 teaches a CD8a signal sequence (also referred to as a CD8a leader) comprising amino acid sequence SEQ ID NO: 628 (page 127, [00274]; page 76), which is identical to instant SEQ ID NO: 161 as shown in the ABSS alignment below.
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It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the bicistronic iCAR/aCAR construct taught by the combination of WO’012 and WO’099 to further include a signal peptide, including the CD8 alpha signal peptide, as disclosed by AU’583. An ordinarily skilled artisan would have been motivated to further include the signal peptide in order to direct the iCAR and/or aCAR to the surface of the immune cell. An ordinarily skilled artisan would have had a reasonable expectation of success as all of WO’012, WO’099, and AU’583 are drawn to CAR constructs and expression of CARs.
Claims 179, 183, 185, and 189 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/061012 A1 (Gross, G., et al) 05 Apr 2018 as applied to claim 1 above, and in further view of AU 2018/227583 B2 (Suri, V., et al) 07 Sept 2018, WO 2019/056099 A1 (Levings, M., et al) 28 Mar 2019, NCBI reference sequence: NM_006669.6, Homo sapiens leukocyte immunoglobulin like receptor B1 (LILRB1), transcript variant 1, mRNA, PRI 31-May-2020, WO 2014/018572 A2 (Dixit, S.B., et al) 03 Jan 2014, and CA 3 133 333 A1 (Garrison, B.S., et al) 30 Apr 2020.
WO’012 teaches the iCAR/aCAR bicistronic construct of claim 1 as discussed in detail above.
As discussed above, WO’012 teaches that the iCAR comprises an scFv, including one that binds to HLA-A2, including VH and VL from BB7.2; a flexible hinge and transmembrane domain; and an intracellular signaling domain that inhibits the effector immune cell, including the intracellular signaling domain from LIR1. WO’012 further teaches that the aCAR comprises an scFv that targets an antigen, including HER2; a hinge and transmembrane domain; a co-stimulatory domain, including that from 4-1BB; and an intracellular signaling domain homologous to an ITAM including CD3ζ. WO’012 also teaches that the vector encoding the biscistronic iCAR/aCAR can comprise self-cleaving 2A peptides between the sequences including T2A (page 70, claims 16-17).
WO’012, however, does not disclose that the iCAR/aCAR constructs comprise an amino acid sequence selected from those recited in the instant claims.
The teachings of AU’583 are as discussed above. As discussed above, AU’583 teaches that signal peptides can be used to direct a payload to the surface of a T cell such that the payload is presented on the surface of the cell. AU’583 also teaches that the signal peptide can be from CD8α, and can be SEQ ID NO: 628 (page 127, [00274]; page 76). AU’583, SEQ ID NO: 628 is identical to the signal peptides for both the iCAR and aCAR in instant SEQ ID NO: 26, specifically the sequence is identical to instant SEQ ID NO: 26, amino acids 1-21 and 526-546.
AU’583 further teaches hinge, transmembrane, co-stimulatory, and intracellular signaling domains that are typically used in CAR production.
AU’583 teaches that a hinge sequence is a short sequence of amino acids that facilitates flexibility of the extracellular targeting domain that moves the target binding domain away from the effector cell surface to enable proper cell/cell contact, target binding, and effector cell activation. The hinge can be an extracellular region of type 1 membrane proteins, such as CD8α or CD28 (pages 63-64, [00222]). AU’583 also teaches that CARs comprise a transmembrane domain which can be selected from transmembrane regions including those form CD28 or CD8α (page 63, [00219]). AU’583 teaches a CD28 hinge and transmembrane domain of SEQ ID NO: 384 (page 64 and 68), which is identical to instant SEQ ID NO: 26, amino acids 267-332, as shown in the ABSS alignment below:
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AU’583 further teaches a CD8α hinge and transmembrane sequence of SEQ ID NO: 625 (page 75), which is identical to instant SEQ ID NO: 26, amino acids 792-860, as shown in the ABSS alignment below:
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AU’583 further teaches a sequence for a 4-1BB co-stimulatory domain in combination with a CD3 zeta signaling domain of SEQ ID NO: 290 (page ), which is identical to instant SEQ ID NO: 26, amino acids 861-1014, as shown in the ABSS alignment below:
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The teachings of WO’099 are as discussed above. As discussed above, WO’099 teaches the heavy and light chain variable regions of the BB7.2 antibody as well as the use of a (Gly4Ser)3 linker in the formation of an scFv. An scFv comprising the VH and VL of BB7.2 and the (Gly4Ser)3 linker are identical to instant SEQ ID NO: 26, amino acids 22-266, as shown in the ABSS alignment below:
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The teachings of NM_006669.6 are as discussed above. As discussed above, NM_006669.6 provides the amino acid sequence of the ILR1 gene on page 4, which comprises an intracellular signaling domain that is identical to instant SEQ ID NO: 26, amino acids 333-500, as shown in the alignment below:
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The teachings of WO’572 are as discussed above and, as discussed above teach an anti-HER2 scFv of SEQ ID NO: 172. The anti-HER2 ScFv of WO’572 is identical to instant SEQ ID NO: 26, amino acids 547-791, as shown in the alignment below:
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CA’333 teaches isolated immunoresponsive cells comprising two chimeric antigen receptors (page 2, [0005]) and teaches a single nucleic acid encoding the two or more CARs under a single or separate regulatory control elements. In some embodiments, a single nucleic acid encodes the two or more CARs in the same reading frame and are expressed as a single polypeptide chain. The two or more CARs may be separated by one or more peptide cleavage sites, such as auto-cleavage sites or substrates for intracellular protease. Suitable peptide cleavage sites may include, without limitation, a T2A peptide cleavage site (page 136, [0582]). CA’333 further teaches exemplary constructs in which the T2A cleavage site is used and comprises a sequence of RRKRGSGEGRGSLLTCGDVEENPGP, see for instance the constructs of SEQ ID NO: 198, page 237 and SEQ ID NO: 200, page 239). This sequence for the T2A cleavage site is identical to instant SEQ ID NO: 26, amino acids 501-525, as shown in the alignment below:
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It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to construct the iCAR/aCAR bicistronic vector disclosed by WO’012 using the known sequences disclosed by AU’583, WO’099, NM_006669.6, WO’572, and CA’333 for each of the components already disclosed by WO’012. It would have further been obvious to further include a CD8a signal peptide based on the teachings of AU’583. It would have been obvious to use the sequences taught by AU’583, WO’099, NM_006669.6, WO’572, and CA’333 as the sequences are known sequences for the domains already taught by WO’012 for inclusion in the CAR suggesting that they would have analogous properties. An ordinarily skilled artisan would have been motivated to further include the signal peptide in order to direct the iCAR and aCAR to the surface of the immune cell. An ordinarily skilled artisan would have had a reasonable expectation of success as all of AU’583 teaches the use of the signal peptide in the construction of CARs. Using these known sequences to construct the iCAR/aCAR results in a construct that is identical to instant SEQ ID NO: 26, as shown in instant Table 1 for the construct VR292.
Claim 184 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/061012 A1 (Gross, G., et al) 05 Apr 2018 as applied to claim 1 above, and in further view of AU 2018/227583 B2 (Suri, V., et al) 07 Sept 2018, WO 2019/056099 A1 (Levings, M., et al) 28 Mar 2019, NCBI reference sequence: NM_006669.6, Homo sapiens leukocyte immunoglobulin like receptor B1 (LILRB1), transcript variant 1, mRNA, PRI 31-May-2020, WO 2014/018572 A2 (Dixit, S.B., et al) 03 Jan 2014, CA 3 133 333 A1 (Garrison, B.S., et al) 30 Apr 2020, US 7,169,894 B2 (Martin, M.T.) 30 January 2007, and Gould, N., et al (2014) Computational tools and algorithms for designing and customized synthetic genes Frontiers in Bioengineering and Biotechnology 2(41); 1-14.
WO’012 teaches the iCAR/aCAR bicistronic construct of claim 1 as discussed in detail above.
WO’012, however, does not disclose that the construct comprises a nucleotide sequence from table 1, including those recited.
The teachings of AU’583, WO’099, NM_006669.6, WO’572, and CA’333 are as discussed above and, in combination with WO’012, teach an iCAR/aCAR construct of SEQ ID NO: 26, as discussed in detail in the rejection above regarding claim 179.
The instant disclosure identifies instant SEQ ID NO: 25 as the nucleic acid sequence that encodes SEQ ID NO: 26. While the combination of applied references does not teach the nucleic acid sequence that encodes the construct of SEQ ID NO: 26, the reverse translation of amino acid sequences to obtain the nucleic acid sequences that encode them is considered to be routine in the art.
For instance, US’894 discusses processes through which polynucleotides are synthesized from a specific peptide or protein that they encode both through traditional techniques and via processes where sequence analysis of the peptide is not required (abstract; column 3, lines 5-17). US’894 teaches that reverse translation is the step of informational coupling of individual amino acids to their corresponding codons. Natural codons are trinucleotides and the three-nucleotide sequences of a codon specifies, or encodes, a specific amino acid (column 9, lines 29-33; Figure 1). There are 20 genetic code-encoded amino acids with 64 amino acid-encoding codons in the natural genetic code (column 18, lines 4-7; Figure 1). US’894 teaches that synthesis of an encoding polynucleotide, including RNA or DNA, that encodes a specific peptide or protein conventionally involves purifying a peptide or protein and sequencing it using an automated amino acid sequencing machine. Following sequencing, the identity and order of the amino acids are read and an oligonucleotide is synthesized using a second instrument, an oligonucleotide synthesizer. From the prepared oligo, the full-length polynucleotide can be cloned and the protein can be produced (column 3, lines 5-17).
Gould teaches that advances in DNA synthesis have enabled the construction of artificial genes and freedom in de novo design of synthetic constructs. To aid this goal, a large number of software tools of variable sophistication have been implemented enabling the design of synthetic genes for sequence optimization based on rationally designed properties. Gould teaches that years recent to the publication had seen the emergence of sequence design tools that aim to evolve sequences toward combinations of objectives. Gould provides a review of the approaches that different tools have adopted to redesign genes and optimize desired coding features and discusses their strengths and limitations (abstract). Gould provides a review of the most important objectives in synthetic gene design towards optimized expression as well as a review of 11 gene design tools that were available at the time of publication that incorporate the aforementioned objectives (page 1, right column, paragraph 3; page 4, table 1). The gene design tools disclosed can be used to translate and optimize DNA sequences without altering the chain of amino acids (page 4, left column, paragraph 2).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to use the sequences disclosed by the combination of AU’583, WO’099, NM_006669.6, WO’572, and CA’333 in the iCAR/aCAR construct of WO’012 to arrive at instantly claimed SEQ ID NO: 26 as discussed in detail above. it would have further been obvious to use reverse translation techniques that are routine in the art, such as the methods of US’894 and/or the computational tools disclosed by Gould, to reverse translate the amino acid sequence into a nucleic acid sequence for encoding the iCAR/aCAR construct. This conclusion of obviousness is further supported by KSR(E) obvious to try. In this case, the combination of applied references teaches an iCAR/aCAR construct with an amino acid sequence that is identical to instant SEQ ID NO: 26. US’894 teaches that there are 20 genetically encoded amino acids with 64 amino acid-encoding codons and both US’894 and Gould demonstrate that reverse translation was commonly practiced in the art of protein and gene synthesis. An ordinarily skilled artisan would have been able to pursue the known potential solutions with a reasonable expectation that the resulting nucleic acid would encode the amino acid sequence that it was reverse translated from, specifically that of SEQ ID NO: 26.
Claims 186-187 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/061012 A1 (Gross, G., et al) 05 Apr 2018 as applied to claim 1 above, and in further view of AU 2018/227583 B2 (Suri, V., et al) 07 Sept 2018, US 2018/0208636 A1 (Wendell, A.L., et al) 26 Jul 2018, WO 2019/056099 A1 (Levings, M., et al) 28 Mar 2019, and NCBI Reference sequence XM_006712573.1 Homo sapiens programmed cell death 1 (PDCD1), transcript variant X1, mRNA PRI 03-Feb-2014,
WO’012 teaches the iCAR/aCAR bicistronic construct of claim 1 as discussed in detail above.
As discussed above, WO’012 teaches that the iCAR comprises an scFv, including one that binds to HLA-A2, including VH and VL from BB7.2; a flexible hinge and transmembrane domain; and an intracellular signaling domain that inhibits the effector immune cell, including the intracellular signaling domain from PD1. WO’012 further teaches an embodiment in which the transmembrane and intracellular domains up to the first annotated extracellular domain of PD-1, identified as amino acids 145-288, are fused downstream to the HLA-A2-scFv (page 49, lines 28-31). WO’012 further teaches that the genes can be fused to a protein tag, such as HA, Flag, or Myc (page 50, lines 24-28).
WO’012, however, does not disclose that the iCAR comprises a sequence disclosed in instant claim 186.
The teachings of AU’583 are as discussed above. As discussed above, AU’583 teaches that signal peptides can be used to direct a payload to the surface of a T cell such that the payload is presented on the surface of the cell. AU’583 also teaches that the signal peptide can be from CD8α, and can be SEQ ID NO: 628 (page 127, [00274]; page 76). AU’583, SEQ ID NO: 628 is identical to the signal peptide in instant SEQ ID NO: 261, amino acids 1-21, as shown in the alignment below:
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US’636 teaches binding triggered transcriptional switch receptor polypeptides and host cells genetically modified with nucleic acids encoding the chimeric receptor polypeptides (abstract). US’636 exemplifies receptors comprising a CD8a signal peptide and a myc-tag of EQKLISEEDL (SEQ ID NO: 75) for easy determination of surface expression (pages 83-84, [0687]). The examples provided by US’636 demonstrate the inclusion of the myc-tag between the signal peptide and the scFv (for instance, see Figs. 17b-c, 19b, and 20-28). The myc-tag sequence disclosed by US’636 is identical to instant SEQ ID NO: 261, amino acids 22-31, as shown in the alignment below:
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The teachings of WO’099 are as discussed above. As discussed above, WO’099 teaches the heavy and light chain variable regions of the BB7.2 antibody as well as the use of a (Gly4Ser)3 linker in the formation of an scFv. An scFv comprising the VH and VL of BB7.2 and the (Gly4Ser)3 linker are identical to instant SEQ ID NO: 261, amino acids 32-276, as shown in the ABSS alignment below:
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XM_006712573.1 provides the amino acid sequence of PD-1. Amino acids 145-288 of PD-1, as specified by WO’012, are identical to instant SEQ ID NO: 261, amino acids 277-330, as shown in the alignment below:
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It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to construct the iCAR in the iCAR/aCAR bicistronic vector disclosed by WO’012 using the known sequences disclosed by AU’583, US’636, WO’099, and XM_006712573.1 for each of the components already disclosed by WO’012. It would have further been obvious to further include a CD8a signal peptide based on the teachings of AU’583. It would have been obvious to use the sequences taught by AU’583, US’636, WO’099, and XM_006712573.1 as the sequences are known sequences for the domains already taught by WO’012 for inclusion in the CAR suggesting that they would have analogous properties. An ordinarily skilled artisan would have been motivated to further include the signal peptide in order to direct the iCAR to the surface of the immune cell. An ordinarily skilled artisan would have had a reasonable expectation of success as all of AU’583 teaches the use of the signal peptide in the construction of CARs. Using these known sequences to construct the iCAR results in a construct that is identical to instant SEQ ID NO: 261, which is comprised in instant Table 12.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
US 11,660,315
Claims 1-6, 11, 45, 51, 64, 68, 71, 114, 124-126, 163, 165-167, 170-171, 175, 179-181, and 183-202 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11,660,315 in view of WO’012, AU’583, WO’099, NM_006669.6, WO’572, CA’333, AB673344.1, US’894, Gould, US’636, and XM_006712573.1.
US’315 claims a method for preparing a safe effector immune cell expressing (i) an inhibitory CAR (iCAR) or a protective CAR (pCAR) and (ii) an activating CAR (aCAR), the method comprising: identifying a gene with at least two expressed alleles that encode a protein comprising an extracellular polymorphic epitope; determining that at least one of the expressed alleles exhibit an amino acid sequence change in the extracellular polymorphic epitope sequence relative to a reference sequence; determining that the gene is located in a chromosomal region that undergoes LOH in a tumor type; and determining that the gene is expressed in the tissue of origin of the tumor type in a region found to undergo LOH. US’315 claims that the aCAR is directed, or specifically binds to, a TAA or non-polymorphic cell surface epitope, including a target selected from a group that includes HER2. US’315 further claims that the aCAR is directed against or specifically binds to a cell surface protein that is expressed in a tumor tissue in which the iCAR is also expressed. US’315 claims that the gene comprising the extracellular polymorphic epitope is an HLA gene, comprising HLA-A, HLA-B, HLA-G, HLA-E, HLA-F, HLA-K, HLA-L, HLA-DM, HLA-DO, HLA-DP, HLA-DQ, and HLA-DR genes. US’315teaches that the tumor type is breast, prostate, ovarian, cervical, skin, pancreatic, colorectal, renal, liver, or brain tumors or a lymphoma, leukemia, lung tumor, or glioma.
US’315 differs from the instantly claimed invention in that US’315 does not claim a bicistronic iCAR/aCAR or monocistronic constructs, the specific domains that are within the iCAR/aCAR, or the sequences of the instantly claimed invention.
The teachings of WO’012, AU’583, WO’099, NM_006669.6, WO’572, CA’333, AB673344.1, US’894, Gould, US’636, and XM_006712573.1 are as discussed in detail above and, as discussed in detail above, render obvious the instantly claimed structures.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’315 to include the instantly claimed structures as the combination of WO’012, AU’583, WO’099, NM_006669.6, WO’572, CA’333, AB673344.1, US’894, Gould, US’636, and XM_006712573.1 demonstrate that the structures were known in the prior art concerning CAR construction including for the construction of iCAR/aCAR constructs. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
16/586,730
Claims 1-6, 11, 45, 51, 64, 68, 71, 114, 124-126, 163, 165-167, 170-171, 175, 179-181, and 183-202 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, 6, 109-111, and 113-123 of copending Application No. 16/586,730 in view of in view of WO’012, AU’583, WO’099, NM_006669.6, WO’572, CA’333, AB673344.1, US’894, Gould, US’636, and XM_006712573.1.
App’730 claims a method of identifying a CAR pair comprising selecting a first inhibitory CAR (iCAR) or protective CAR (pCAR), wherein selecting comprises selecting an antigen binding domain known to be specific for a target extracellular polymorphic epitope from an HLA gene or screening for such; selecting an intracellular domain from an inhibitory receptor that is known to antagonize activation of an effector cell; and building an iCAR comprising the binding domain and intracellular domain; selecting a second CAR that is an activating Car capable of inducing activation, comprising selecting an aCAR known to induce activation of an effector T cell or building an a CAR that binds to a cell surface protein selected from a list which includes HER2, selecting a known intracellular T cell activating signal transduction element and building an aCAR from the binding domain and signal transduction element; expressing the first and second CAR in a population of effector T cells, contacting the effector T cells separately with cell types expressing the targets, and measuring activation, and identifying a CAR pair that prevents or attenuates activation of effector T cells against the cells. App’730 further claims that the HLA gene is located in a chromosomal region that exhibits LOH, as the result of SNP, where the HLA gene is an HLA-A, HLA-B, HLA-C, HLA-G, HLA-E, HLA-F, HLA-DPA1, HLA-DQA1, HLA-DQB1, HLA-DBQ2, HLA-DRB1, or HLA-DRB5. App’730 claims that the second type of cell (that is targeted by the aCAR) is a cancer cell selected from the group consisting of breast, prostate, ovarian, cervical, skin, pancreatic, colorectal, renal, liver, brain, lymphoma, leukemia, and lung cancer.
App’730 differs from the instantly claimed invention in that App’730 does not claim a bicistronic iCAR/aCAR or monocistronic constructs, the specific domains that are within the iCAR/aCAR, or the sequences of the instantly claimed invention.
The teachings of WO’012, AU’583, WO’099, NM_006669.6, WO’572, CA’333, AB673344.1, US’894, Gould, US’636, and XM_006712573.1 are as discussed in detail above and, as discussed in detail above, render obvious the instantly claimed structures and methods.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of App’730 to include the instantly claimed structures and methods as the combination of WO’012, AU’583, WO’099, NM_006669.6, WO’572, CA’333, AB673344.1, US’894, Gould, US’636, and XM_006712573.1 demonstrate that the structures were known in the prior art concerning CAR construction including for the construction of iCAR/aCAR constructs and methods of use thereof. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
18/704,224
Claims 1-6, 11, 45, 51, 64, 68, 71, 114, 124-126, 163, 165-167, 170-171, 175, 179-181, and 183-202 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 10, 12, 14, 16, 18, 20-23, 25-27, and 29-30 of copending Application No. 18/704,224 in view of WO’012, AU’583, WO’099, NM_006669.6, WO’572, CA’333, AB673344.1, US’894, Gould, US’636, and XM_006712573.1.
App’224 claims a population of CD4+, CD8+ cells, or a combination thereof comprising a bicistronic iCAR/aCAR nucleotide construct which encodes:
An iCAR portion comprising: an iCAR scFv, optionally in the VH-VL or VL-VH orientation, comprising a first linker, wherein the iCAR targets a first antigen; an iCAR hinge domain component; an iCAR transmembrane domain component; and
An aCAR portion comprising: an aCAR-scFv component, optionally in the VH-VL or VL-VH orientation, comprising a second linker, wherein the aCAR scFv targets a second antigen; an aCAR hinge component, an aCAR TM domain component; an aCAR co-stimulatory domain component; and an aCAR activation signaling domain; and
The bicistronic construct comprises a third linker that connects the iCAR in (i) to the aCAR in (ii).
App’224 further claims that the first and/or second linker comprises linkers selected from the group consisting of (G4S)X3 linker (SEQ ID NO: 81), G4S linker (SEQ ID NO: 153), (G4S)X3 (SEQ ID NO: 154, and Whitlow linker.
App’224 further claims that the iCAR scFv component targets an HLA antigen, including those selected from a group that is the same as instant claim 4, and that the iCAR scFv component is selected from a group that is identical to instant claim 5. App’224 further claims that the iCAR scFv component comprises or consists essentially of Hz BB7.2.1 or SN66E3.3. App’224 further claims that the iCAR hinge is selected from LIR1 52aa hinge, LIR1 36aa hinge, LIR130 aa hinge, LIR1 26 aa hinge, or a LIR1 8 aa hinge, and that the inhibitory domain is selected from LIR1, LIR2, LIR3, LIR5, or LIR8, including an inhibitory domain of LIR1 SEQ ID NO: 143. App’224 further claims that the aCAR comprises or consists of the VH/VL of trastuzumab and that the scFv comprises or consists of SEQ ID NO: 172. App’224 further claims that the aCAR hinge TM domain is an CD8 alpha hinge domain of SEQ ID NO: 84. App’224 claims that the aCAR costimulatory domain is selected from the group consisting of 4-1BB, CD28, CD28BB, and CD3 zeta costimulatory domain, with the sequences recited. App’224 further claims that the linker connecting the iCAR and aCAR consists essentially of or is a T2A of SEQ ID NOs: 155 or IRES sequence of SEQ ID NOs: 159 or 160. App’224 further claims that the construct comprises the nucleic acid sequence selected from the group consisting of SEQ ID NO: 277 or 279, with a nucleotide sequence comprising SEQ ID NOs: 240, 241, or 242. App’224 further claims that the iCAR/aCAR construct further comprises a nucleotide sequence that encodes a CD8 alpha signal peptide as set forth in SEQ ID NO: 161.
The claims of App’224 anticipate instant claims 1-6, 11, 45, 51, 64, 68, 71, 114, 124-126, 163, 165-167, 170-171, 175, 183, and 187-199.
Additionally, while App’224 differs from the instantly claimed invention in that the instantly claimed invention includes additional structures as well as methods of treating cancer in a patient using the iCAR/aCAR construct expressing effector cells, these additions to the claims of App’224 would have been obvious in view of the teachings of the prior art.
The teachings of WO’012, AU’583, WO’099, NM_006669.6, WO’572, CA’333, AB673344.1, US’894, Gould, US’636, and XM_006712573.1 are as discussed in detail above and, as discussed in detail above, render obvious the instantly claimed structures and methods.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of App’224 to include the instantly claimed structures and methods as the combination of WO’012, AU’583, WO’099, NM_006669.6, WO’572, CA’333, AB673344.1, US’894, Gould, US’636, and XM_006712573.1 demonstrate that the structures were known in the prior art concerning CAR construction including for the construction of iCAR/aCAR constructs and methods of use thereof. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693