DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s species election without traverse in the REMARKS filed on December 29, 2025 is acknowledged.
The elected species are:
i) CD30 as the targeted antigen and SEQ ID NOs: 14 and 15 for the antigen binding domain.
ii) SEQ ID NO:26 as the signaling domain,
iii) CD28 as the molecule and SEQ ID NO:20 as the transmembrane domain,
iv) CD35 as the amino acid sequence for the CAR.
Claims 1, 2, 5, 6, 8-11, 14-16, 20-27, 30-34, and 36 have been canceled.
Claims 3, 4, 7, 12, 13, 17-19, 28, 29, 35, and 37-44 are pending.
Claims 29, 39, and 43 have been withdrawn under 37 CFR 1.142(b) as being drawn to nonelected species.
Claims 3, 4, 7, 12, 13, 17-19, 28, 35, 37, 38, 40-42, and 44 are currently under consideration as they read on the elected species.
3. The instant specification discloses:
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Applicant is required to update this paragraph because the sequence submitted has been converted to Version 1.2 which is the current working copy:
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280
1538
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An example of the required paragraph is as follows: “The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on October 26, 2022, is named 17997171_1_2.txt and is 63831 bytes in size.”
4. 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.
5. Claims 3, 4, 7, 12, 13, 17-19, 28, 35, 37, 38, 40-42, and 44 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.
A) The claims are indefinite in the recitation of “optionally” in independent claims 3, 12, 18, and dependent claims 19, 37, and 41 because it is not clear if the alternatives after the word “optionally” are covered by the claims, thereby causing ambiguity. For example, independent claim 12 recites “an amino acid sequence derived from intracellular domain of CD28, optionally wherein the amino acid sequence derived from intracellular domain of CD28 comprising an amino acid sequence having at least 80% amino acid sequence identity to SEQ ID NO:26”. The structure of the recited amino acid sequence is unclear. Is it the intracellular domain of CD28 or partial domain that is SEQ ID NO:26?
For the purpose of examination and application of prior art, the limitations after the word “optionally” are not considered since it is optional.
B) claim 18 is indefinite in the recitation of “or nucleic acid encoding a CAR for use in a method of treating or preventing a disease or condition …..” because it merely recites a use without any active, positive steps delimiting how this use is actually practiced. See MPEP 2173.05(q).
6. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
7. Claims 3, 4, 7, 12, 13, 17-19, 28, 35, 37, 38, 40-42, and 44 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed.Cir.1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of the skilled in the art to practice the claimed invention.
Independent claim 3 and dependent claims thereof are draw to a method of treating or preventing a disease or condition characterized by an alloreactive immune response by administering to a subject a therapeutically or prophylactically effective quantity of virus-specific immune cells comprising a chimeric antigen receptor (CAR) comprising:
i) an antigen binding domain that specifically binds CD30,
ii) a transmembrane domain,
iii) a signaling domain comprising:
(a) an amino acid sequence derived from the intracellular domain of CD28
(b) an amino acid sequence comprising an immunoreceptor tyrosine-based activation motif (ITAM)
Independent claim 12 and dependent claims thereof are drawn to a method of treating or preventing a disease or condition by allotransplantation by administering to a subject a therapeutically or prophylactically effective quantity of virus-specific immune cells comprising a CAR or nucleic acid encoding a CAR comprising:
i) an antigen binding domain that specifically binds CD30,
ii) a transmembrane domain,
iii) a signaling domain comprising:
(a) an amino acid sequence derived from the intracellular domain of CD28
(b) an amino acid sequence comprising an immunoreceptor tyrosine-based activation motif (ITAM).
Independent claim 18 and dependent claims thereof are drawn to a method of killing alloreactive immune cells by contacting alloreactive immune cells with a virus-specific immune cell comprising a CAR or nucleic acid encoding a CAR for use in a method of treating or preventing a disease or condition characterized by an alloreactive immune response wherein the CAR comprises:
i) an antigen binding domain that specifically binds CD30,
ii) a transmembrane domain,
iii) a signaling domain comprising:
(a) an amino acid sequence derived from the intracellular domain of CD28
(b) an amino acid sequence comprising an immunoreceptor tyrosine-based activation motif (ITAM)
The specification discloses that CAR-expressing virus-specific immune cells refers to an immune cell which is specific for a virus and express a receptor capable of recognizing a peptide of an antigen of virus, e.g. when presented by MHC molecule (e.g. see [0083] of US 20230172986, PGPUB of the instant application). The specification further discloses that EBV virus specific T cells were isolated from PBMCs from healthy donor depleted of CD45RA-expressing cells, following by stimulation of ENNA1 pepmix (e.g. see [0630] of the PGPUB). The EBV virus specific T cells were then transduced with CD30 CAR-encoded retrovirus (e.g. see Examples 1 and 2 in pages 40-41 of the PGPUB). The specification further discloses treatment of CD30+ human lymphoma patients by administering the CD30 CAR EBVST cells (e.g. see 5.2 in page 43 of the PGPUB).
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The instant claims encompass an antigen binding domain that binds CD30, a transmembrane domain, and a signaling domain comprises an amino acid sequence derived from CD28 and an amino acid sequence comprising ITAM without providing sufficient structure for each of the elements. The specification does not provide sufficient guidance and directions to identify and enable the CAR for the method of treating or preventing a disease or condition characterized by an alloreactive immune response or killing alloreactive immune cells.
There does not appear to be sufficient guidance in the specification as filed as to how the skilled artisan would make and use the virus-specific immune cells comprising the CAR or nucleic acid encoding a CAR as recited in the instant methods.
It is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway Jr et al., Immunology, 3rd Edition, 1997 Garland Publishing Inc., pages 3:1-3:11.see entire selection). Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
Artisans are well aware that knowledge of a given antigen (for CD30) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. (J. Mol. Biol., 2003, 334:103-118) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well, see entire document).
Homback et al. (Molecular Therapy 2019, 27;10:1825-1835) teach that antagonistic anti-CD30 scFv CAR can increase immune response of anti-CEA CAR but agonistic anti-CD30 scFv CAR was not effective (e.g. see Abstract).
Further, a CAR comprises an amino acid sequence having at least 80% amino acid sequence identity to the instantly recited SEQ ID NO:35 (in instant claim 28) binds CD19, rather than CD30 (see sequence alignment below):
RESULT 1
US-19-487-852-15
Sequence 15, US/19487852
GENERAL INFORMATION
APPLICANT: Autolus Limited (en)
TITLE OF INVENTION: CD19CAR T-CELL TREATMENT OF RELAPSED/REFRACTORY B-CELL ACUTE LYMPHOBLASTIC LEUKAEMIA (en)
FILE REFERENCE: P127588PCT
CURRENT APPLICATION NUMBER: US/19/487,852
CURRENT FILING DATE: 2025-11-25
NUMBER OF SEQ ID NOS: 51
SEQ ID NO 15
LENGTH: 681
TYPE: PRT
FEATURE:
NAME/KEY: source
LOCATION: 1..681
QUALIFIERS: mol_type = protein
organism = synthetic construct
Query Match 84.6%; Score 3033; Length 681;
Best Local Similarity 85.9%;
Matches 572; Conservative 34; Mismatches 54; Indels 6; Gaps 3;
Qy 1 QVQLQQSGAELARPGASVKMSCKASGYTFTTYTIHWVRRRPGHDLEWIGYINPSSGCSDY 60
|||||||| || :||||||:||||||| |:: ::||::||| ||||| | | ::|
Db 22 QVQLQQSGPELVKPGASVKISCKASGYAFSSSWMNWVKQRPGKGLEWIGRIYPGDEDTNY 81
Qy 61 NQNFKGKTTLTADKSSNTAYMQLNSLTSEDSAVYYCARRADYGNYEYTWFAYWGQGTTVT 120
: || | |||||||| ||||||:||||||||||:||| ||:| |||||||:|
Db 82 SGKFKDKATLTADKSSTTAYMQLSSLTSEDSAVYFCARSLLYGDY----LDYWGQGTTLT 137
Qy 121 VSSSGGGSGGGGSGGGGSVIELTQSPKFMSTSVGDRVNVTYKASQNVGTNVAWFQQKPGQ 180
||| |||||||||||||| | ||||| || | |::| :| || :| : : |:||| |
Db 138 VSSGGGGSGGGGSGGGGSQIVLTQSPAIMSASPGEKVTMTCSASSSV-SYMHWYQQKSGT 196
Qy 181 SPKVLIYSASYRYSGVPDRFTGSGSGTDFTLTISNVQSEDLAEYFCQQYHTYPLTFGGGT 240
||| || | |||||||:|||||| : |||:|:::|| | |:|||:: ||||| ||
Db 197 SPKRWIYDTSKLASGVPDRFSGSGSGTSYFLTINNMEAEDAATYYCQQWNINPLTFGAGT 256
As such, there is insufficient objective evidence that CAR comprising the anti-CD30 antibody comprising VH of SEQ ID NO:14 and VL of SEQ ID NO:15, a transmembrane domain of SEQ ID NO:20 (from CD28), and a signaling domain of SEQ ID NO:26 from intracellular domain of CD28 as disclosed in the instant specification can be extrapolated to enable for a CAR comprising an antigen-binding domain that binds CD30 or at least 80% identical to SEQ ID NOs: 14 and 15, any transmembrane domain or at least 80% identical to SEQ ID NO:20, an signaling domain that is 80% identical to SEQ ID NO:26 in a method of treating or preventing a disease or condition by allotransplantation or killing alloreactive immune cells.
There is insufficient guidance and direction in the instant specification regarding which of the amino acids within SEQ ID NOs 14, 15, 20, and 26 can be changed in order to maintain the functions of the CAR.
Moreover, the burden of enabling the prevention of a diseases characterized by an alloreactive immune response would be greater than that of enabling a treatment due to the need to screen those humans susceptible to such diseases and the difficulty of proof that the administration of the drug was the agent that acted to prevent the condition.
In addition, the specification does not provide guidance as to how one skilled in the art would go about screening those patients having a disease or condition characterized by an alloreactive immune response. Nor is guidance provided as to a specific protocol to be utilized in order to prove the efficacy of the presently claimed virus-specific immune cells in preventing these diseases. Additionally, the specification fails to enable “treating” to the extent such treatment includes the prevention of a disease state. Accordingly, undue experimentation is necessary to determine screening and testing protocols to demonstrate the efficacy of the presently claimed invention.
8. Claims 3, 4, 7, 12, 13, 17-19, 28, 35, 37, 38, 40-42, and 44 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Independent claim 3 and dependent claims thereof are draw to a method of treating or preventing a disease or condition characterized by an alloreactive immune response by administering to a subject a therapeutically or prophylactically effective quantity of virus-specific immune cells comprising a chimeric antigen receptor (CAR) comprising:
i) an antigen binding domain that specifically binds CD30,
ii) a transmembrane domain,
iii) a signaling domain comprising:
(a) an amino acid sequence derived from the intracellular domain of CD28
(b) an amino acid sequence comprising an immunoreceptor tyrosine-based activation motif (ITAM).
Independent claim 12 and dependent claims thereof are drawn to a method of treating or preventing a disease or condition by allotransplantation by administering to a subject a therapeutically or prophylactically effective quantity of virus-specific immune cells comprising a CAR or nucleic acid encoding a CAR comprising:
i) an antigen binding domain that specifically binds CD30,
ii) a transmembrane domain,
iii) a signaling domain comprising:
(a) an amino acid sequence derived from the intracellular domain of CD28
(b) an amino acid sequence comprising an immunoreceptor tyrosine-based activation motif (ITAM).
Independent claim 18 and dependent claims thereof are drawn to a method of killing alloreactive immune cells by contacting alloreactive immune cells with a virus-specific immune cell comprising a CAR or nucleic acid encoding a CAR for use in a method of treating or preventing a disease or condition characterized by an alloreactive immune response wherein the CAR comprises:
i) an antigen binding domain that specifically binds CD30,
ii) a transmembrane domain,
iii) a signaling domain comprising:
(a) an amino acid sequence derived from the intracellular domain of CD28
(b) an amino acid sequence comprising an immunoreceptor tyrosine-based activation motif (ITAM).
Dependent claims 19, 37, and 41 further limits the signaling domain to comprises an amino acid sequence that is at least 80% identical to SEQ ID NO:26, or the transmembrane domain derived from the transmembrane domain of CD28 that the at least 80% identical to SEQ ID NO:20, or he antigen binding domain comprises amino acid sequences that are at least 80% identical to SEQ ID NOs: 14 and 15, respectively.
The specification discloses that CAR-expressing virus-specific immune cells refers to an immune cell which is specific for a virus and express a receptor capable of recognizing a peptide of an antigen of virus, e.g. when presented by MHC molecule (e.g. see [0083] of US 20230172986, PGPUB of the instant application). The specification further discloses that EBV virus specific T cells were isolated from PBMCs from healthy donor depleted of CD45RA-expressing cells, following by stimulation of ENNA1 pepmix (e.g. see [0630] of the PGPUB). The EBV virus specific T cells were then transduced with CD30 CAR-encoded retrovirus (e.g. see Examples 1 and 2 in pages 40-41 of the PGPUB). The specification further discloses treatment of CD30+ human lymphoma patients by administering the CD30 CAR EBVST cells (e.g. see 5.2 in page 43 of the PGPUB).
There is insufficient written description in the specification as-filed of virus-specific immune cells comprising a CAR or nucleic acid encoding a CAR as recited in the instant claims.
The claims recite a genus of the virus-specific immune cells comprising a CAR or nucleic acid encoding a CAR as part of the invention without providing a physical structure or testable functional activity for the components of the CAR which encompass i) an antigen binding domain that specifically binds CD30, ii) a transmembrane domain, iii) a signaling domain comprising: (a) an amino acid sequence derived from the intracellular domain of CD28
(b) an amino acid sequence comprising an immunoreceptor tyrosine-based activation motif (ITAM), or a CAR comprises the signaling domain to comprises an amino acid sequence that is at least 80% identical to SEQ ID NO:26, or the transmembrane domain derived from the transmembrane domain of CD28 that the at least 80% identical to SEQ ID NO:20, or he antigen binding domain comprises amino acid sequences that are at least 80% identical to SEQ ID NOs: 14 and 15, respectively.
The genus of the CAR or nucleic acid encoding the CAR are therefore extremely large. Applicant has disclosed a CAR comprising anti-CD30 antibody comprising SEQ ID NOs: 14, and 15, a transmembrane domain comprising SEQ ID NO:20 and a signaling domain comprising SEQ ID NO:26. Thus Applicant has disclosed only a limited species of the CD30 CAR. The claimed CAR or nucleic acid encoding the CAR lack a common structure essential for their function and the claims do not require any particular structure basis or testable functions be shared by the instant CAR.
It is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway Jr et al., Immunology, 3rd Edition, 1997 Garland Publishing Inc., pages 3:1-3:11. see entire selection). Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
Artisans are well aware that knowledge of a given antigen (for CD30) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. (J. Mol. Biol., 2003, 334:103-118) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well, see entire document).
Homback et al. (Molecular Therapy 2019, 27;10:1825-1835) teach that antagonistic anti-CD30 scFv CAR can increase immune response of anti-CEA CAR but agonistic anti-CD30 scFv CAR was not effective (e.g. see Abstract).
Further, a CAR comprises an amino acid sequence having at least 80% amino acid sequence identity to the instantly recited SEQ ID NO:35 (in instant claim 28) binds CD19, rather than CD30 (see sequence alignment below):
RESULT 1
US-19-487-852-15
Sequence 15, US/19487852
GENERAL INFORMATION
APPLICANT: Autolus Limited (en)
TITLE OF INVENTION: CD19CAR T-CELL TREATMENT OF RELAPSED/REFRACTORY B-CELL ACUTE LYMPHOBLASTIC LEUKAEMIA (en)
FILE REFERENCE: P127588PCT
CURRENT APPLICATION NUMBER: US/19/487,852
CURRENT FILING DATE: 2025-11-25
NUMBER OF SEQ ID NOS: 51
SEQ ID NO 15
LENGTH: 681
TYPE: PRT
FEATURE:
NAME/KEY: source
LOCATION: 1..681
QUALIFIERS: mol_type = protein
organism = synthetic construct
Query Match 84.6%; Score 3033; Length 681;
Best Local Similarity 85.9%;
Matches 572; Conservative 34; Mismatches 54; Indels 6; Gaps 3;
Qy 1 QVQLQQSGAELARPGASVKMSCKASGYTFTTYTIHWVRRRPGHDLEWIGYINPSSGCSDY 60
|||||||| || :||||||:||||||| |:: ::||::||| ||||| | | ::|
Db 22 QVQLQQSGPELVKPGASVKISCKASGYAFSSSWMNWVKQRPGKGLEWIGRIYPGDEDTNY 81
Qy 61 NQNFKGKTTLTADKSSNTAYMQLNSLTSEDSAVYYCARRADYGNYEYTWFAYWGQGTTVT 120
: || | |||||||| ||||||:||||||||||:||| ||:| |||||||:|
Db 82 SGKFKDKATLTADKSSTTAYMQLSSLTSEDSAVYFCARSLLYGDY----LDYWGQGTTLT 137
Qy 121 VSSSGGGSGGGGSGGGGSVIELTQSPKFMSTSVGDRVNVTYKASQNVGTNVAWFQQKPGQ 180
||| |||||||||||||| | ||||| || | |::| :| || :| : : |:||| |
Db 138 VSSGGGGSGGGGSGGGGSQIVLTQSPAIMSASPGEKVTMTCSASSSV-SYMHWYQQKSGT 196
Qy 181 SPKVLIYSASYRYSGVPDRFTGSGSGTDFTLTISNVQSEDLAEYFCQQYHTYPLTFGGGT 240
||| || | |||||||:|||||| : |||:|:::|| | |:|||:: ||||| ||
Db 197 SPKRWIYDTSKLASGVPDRFSGSGSGTSYFLTINNMEAEDAATYYCQQWNINPLTFGAGT 256
It is noted that applicant has not claimed a product, but rather a method of administering a product. However, artisans must reasonably be in possession of a product in order to be in possession of methods of administering said product.
Note that none of the instant independent recite any structure for the administered product that provides for the function of CD30 binding and being able to treat or prevent a disease or condition. As to the dependent claims 19, 37, and 41 reciting percent identity to the specific amino acid sequences of each of the component within the CD30 CAR, the instant specification fails to disclose which of the amino acids within SEQ ID NOs 14, 15, 20, and 26 can be changed in order to maintain the functions of the CD30 CAR.
Thus, all present utilize only functional language to describe the product which is necessarily administered in the instant claims.
It is noted that the specification does disclose working examples which utilized a CD30 CAR with specific amino acid sequences for each component. However, this CD30 CAR species is not reasonably representative of the species of all possible CD30 CAR because of the structural diversity found in antibodies that bind the same antigen as discussed above. Further, as has been discussed above, identifying an antibody simply on the basis of what it binds rather than by identifying the sequence/structure of the antibody in question is generally insufficient to provide sufficient written description of the antibody in question.
Therefore, in view of the breadth of the claims and the generic nature of the instant specification, artisans would reasonably conclude that applicant was not in possession of the full breadth of the virus-specific immune cells comprising a CD30 CAR or nucleic acid encoding the CAR at the time the instant application was filed. Logically, if applicant was not in possession of the CAR which is being administered, applicant also was not in possession of methods of administering or contacting such reagents at the time the instant application was filed.
9. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
10. 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.
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.
11. Claims 3, 4, 7, 12, 13, 17-19, 28, 35, 37, 38, 40-42, and 44 are rejected are rejected under 35 U.S.C. 103 as being unpatentable over Chmielews et al. (US 2016/0200824, reference on IDS) in view of Rooney et al. (WO 2018/052947) and Savoldo et al. (Blood 2007, 110(7):2620-2630).
Chmielews et al. teach a CD30 CAR having amino acid sequence of SEQ ID NO:3 that is 98.1% identical to the instantly recited SEQ ID NO:35 (see sequence alignment below, Qy:instant SEQ ID NO:35, Db: prior art SEQ ID NO:3). Also see Fig. 1.
CURRENT APPLICATION NUMBER: US/14/912,937
CURRENT FILING DATE: 2016-02-19
PRIOR APPLICATION NUMBER: EP13181668.8
PRIOR FILING DATE: 2013-08-26
NUMBER OF SEQ ID NOS: 10
SEQ ID NO 3
LENGTH: 690
TYPE: PRT
ORGANISM: artificial sequence
FEATURE:
OTHER INFORMATION: fusion polypeptide
Query Match 98.1%; Score 3517; Length 690;
Best Local Similarity 98.7%;
Matches 658; Conservative 2; Mismatches 5; Indels 2; Gaps 2;
Qy 1 QVQLQQSGAELARPGASVKMSCKASGYTFTTYTIHWVRRRPGHDLEWIGYINPSSGCSDY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 24 QVQLQQSGAELARPGASVKMSCKASGYTFTTYTIHWVRRRPGHDLEWIGYINPSSGCSDY 83
Qy 61 NQNFKGKTTLTADKSSNTAYMQLNSLTSEDSAVYYCARRADYGNYEYTWFAYWGQGTTVT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 84 NQNFKGKTTLTADKSSNTAYMQLNSLTSEDSAVYYCARRADYGNYEYTWFAYWGQGTTVT 143
Qy 121 VSSSGGGSGGGGSGGGGSVIELTQSPKFMSTSVGDRVNVTYKASQNVGTNVAWFQQKPGQ 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 144 VSSSGGGSGGGGSGGGGSVIELTQSPKFMSTSVGDRVNVTYKASQNVGTNVAWFQQKPGQ 203
Qy 181 SPKVLIYSASYRYSGVPDRFTGSGSGTDFTLTISNVQSEDLAEYFCQQYHTYPLTFGGGT 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 204 SPKVLIYSASYRYSGVPDRFTGSGSGTDFTLTISNVQSEDLAEYFCQQYHTYPLTFGGGT 263
Qy 241 KLEIKRSDPAEPKSPDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD 300
||||||||||||||||||||||||||| : |||||||||||||||||:|||||||||||
Db 264 KLEIKRSDPAEPKSPDKTHTCPPCPAPP-VAGPSVFLFPPKPKDTLMIARTPEVTCVVVD 322
Qy 301 VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 323 VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN 382
Qy 361 KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 383 KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG 442
Qy 421 QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 443 QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP 502
Qy 481 GKKDPKFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHY 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 503 GKKDPKFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHY 562
Qy 541 QPYAPPRDFAAYRS-RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEM 599
| || |||||||| |||||||||||||||||||||||||||||||||||||||||||||
Db 563 QAYAAARDFAAYRSLRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEM 622
Qy 600 GGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALH 659
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 623 GGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALH 682
Qy 660 MQALPPR 666
|||||||
Db 683 MQALPPR 689
Further sequence alignment of the instant SEQ ID NO:26 (intracellular domain of CD28) with the prior art SEQ ID NO:3 shows that the prior art SEQ ID NO:3 contains amino acid sequence between amino acid residues 533 to 576 that is 90.3% identical to the instant SEQ ID NO:26 (Qy: instant SEQ ID NO:26, Db: prior art SEQ ID NO:3):
GenCore version 6.5.2
Copyright (c) 1993 - 2026 Biocceleration Ltd.
OM protein - protein search, using sw model
Run on: February 21, 2026, 09:38:03 ; Search time 1 Seconds
(without alignments)
0.030 Million cell updates/sec
Title: US-17-997-171-26
Perfect score: 248
Sequence: 1 FWVRSKRSRLLHSDYMNMTP..........PTRKHYQPYAPPRDFAAYRS 44
Scoring table: BLOSUM62
Gapop 10.0 , Gapext 0.5
Searched: 1 seqs, 690 residues
Total number of hits satisfying chosen parameters: 1
Minimum DB seq length: 0
Maximum DB seq length: inf
Post-processing: Minimum Match 0%
Maximum Match 100%
Listing first 1 summaries
Database : AASEQ2_02212026_093758.pep:*
SUMMARIES
%
Result Query
No. Score Match Length DB ID Description
----------------------------------------------------------------------------
1 224 90.3 690 1 AASEQ2_02212026_093758
ALIGNMENTS
RESULT 1
AASEQ2_02212026_093758
Query Match 90.3%; Score 224; DB 1; Length 690;
Best Local Similarity 93.2%;
Matches 41; Conservative 0; Mismatches 3; Indels 0; Gaps 0;
Qy 1 FWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS 44
||||||||||||||||||||||||||||||| || ||||||||
Db 533 FWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQAYAAARDFAAYRS 576
Therefore, the prior art CD30 CAR of SEQ ID NO:3 contains all component of the instant CD30 CAR including antigen-binding region comprising SEQ ID NO:14 and 14, a transmembrane domain, a signaling domain comprising the amino acid sequence that is 90.3% identical to instant SEQ ID NO:26, an ITAM.
Chmielewski et al. teach a T cell expressing the CAR from nucleic acid encoding the CAR (e.g. see [0045]-[0051]) and the T cells are allogeneic (e.g. see Example 1).
Chmielewski et al. further teach a method of adoptive cell therapy for treating CD30+ cancer in a subject by administering the T cells comprising the CD30 CAR, wherein the T cells are allogeneic (e.g. see claim 22-36).
The reference teachings differ from the instant invention by not describing a virus-specific immune cells comprising the CD30 CAR encoded by the nucleic acid.
However, the platform for activation and expansion of virus-specific CAR T-cells were well-known at the time the instant invention was filed.
For example, Rooney et al. teach that antigen specific T-cell activation and expansion requires three signals: TCR binding to its cognate peptide-MHC complex, stimulation of costimulatory receptor on T-cell surface, and stimulation from cytokines (e.g. see [0004]). Rooney et al. developed virus-specific T cells (VSTs) that serves as CAR T-cell, wherein the virus is EBV virus (e.g. see [0011]-[0015]). Rooney teach PBMCs depleted of CD45RA+ cells from human is the source of T cells (e.g. see [0154] and FIG. 7). Rooney et al. teach CAR-modified T cell can be generated by stimulation AZV specific VST (e.g. see [0164]) and eliminating the need of antigen presenting cells (e.g. see FIG. 22). Rooney et al. teach that the therapeutic T cells modified to express a CAR that targets a cancer antigen including CD30 (e.g. see [0120]). Rooney et al. also teach that the T cells are allogeneic to the individual to be treated for cancer (e.g. see [0123]).
Rooney et al. teach methods of treating an individua in need thereof a medical condition by administering the therapeutic engineered autologous T cells (e.g. see [0041], [0054], [0093], [0120]-[0121]).
Savoldo et al. teach Epstein Barr virus-specific cytotoxic T lymphocytes expressing the anti-CD30 CAR for immunotherapy of Hodgekin’s disease (e.g. see Title). Specifically, Savoldo et al. teach T lymphocytes redirected to eliminate CD30+ tumor cells through the expression of a CAR specifically binding the CD30 molecule can generate a sustained anti-tumor effect (e.g. see paragraph spanning left and right col. in page 2620). However, Savoldo et al. teach the redirected T cells such as CD30 CAR T cells, although functional in vivo, do not expand or persist long term; a problem can be solved by grafting the CAR onto antigen-specific T cells such as EBV-specific cytotoxic T lymphocytes (EBV-CTLs) in order to provide the CAR T cells with stimulation from EBV infected B cells with their native TcR (e.g. see full paragraph in the right col. in page 2620). Savoldo et al. choose EBV because most individuals (humans) are persistently infected with EBV and express viral antigen in epithelial cells and V lymphocytes (e.g. see full paragraph in the right col. in page 2620). Savoldo et al. teach that administering the CAR T cells with their native receptor specific for EBV antigens and CAR for CD30 are particularly useful in treating EBV+ Hodgkin’s Lymphoma since in almost 40% of the HD patients, tumor cells express EBV antigens and administering the CAR T cells would greatly reduce the risk of tumor escape due to EBV antigen or genome loss (e.g. right col. in page 2620).
Savoldo et al teach that the EBV-CTLs were isolated from EBV-seropositive healthy human donors which are allogeneic to patients suffering from Hodgkin’s lymphoma.
It would thus be obvious to one of ordinary skill in the art at the time the instant invention was made to combine the teachings of the references to administer a therapeutically effective amount of EBV-specific T cells comprising CAR that specifically binds CD30, wherein the CAR has the structure of an anti-CD30 antigen-binding domain, a transmembrane domain, and a signaling domain comprising an amino acid sequence that is 80% identical to SEQ ID NO:26, and an ITAM. An ordinary skill in the art would have been motivated to do so, and have a reasonable expectation of success, since Chmielewski et al. each CD30 CAR that is identical to the instantly claimed CD30 CAR for treating cancer and the use of EBV-CTLs for making CAR T cells for expansion and long-term growth in vivo as disclosed by Rooney and Savoldo.
Given that the recited CD30 CAR T cells were readily available as disclosed by Chmielewski et. al, and given that both Rooney and Savoldo teach the benefits of using EBV allogeneic T cells for making CAR T cells including CD30 CAR T cells in in vivo expansion and persistence and provide detailed methods of making allogeneic EBV CAR T cells, an ordinary skill in the art would have been motivated to produce virus-specific CD30 CAR T cells to administer the CD30 CAT T cells to treat CD30+ lymphomas with a reasonable expectation of success. Given the that combined prior art teachings would result in the identical method steps (namely administering to a subject) with the same virus-specific immune cells comprising the same CD30 CAR T cells, the prior art methods would achieve the same results including treating a disease characterized by an alloreactive immune response or killing alloreactive immune cells as recited in the instant claims.
12. 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.
13. Claims 3, 4, 7, 12, 13, 17-19, 28, 35, 37, 38, 40-42, and 44 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5, 7, 9, 11, 14, and 18 of copending USSN 17/997,154 (reference application) in view of Savoldo et al. (Blood 2007, 110(7):2620-2630).
Independent claim 3 and dependent claims thereof are draw to a method of treating or preventing a disease or condition characterized by an alloreactive immune response by administering to a subject a therapeutically or prophylactically effective quantity of virus-specific immune cells comprising a chimeric antigen receptor (CAR) comprising:
i) an antigen binding domain that specifically binds CD30,
ii) a transmembrane domain,
iii) a signaling domain comprising:
(a) an amino acid sequence derived from the intracellular domain of CD28
(b) an amino acid sequence comprising an immunoreceptor tyrosine-based activation motif (ITAM).
Independent claim 12 and dependent claims thereof are drawn to a method of treating or preventing a disease or condition by allotransplantation by administering to a subject a therapeutically or prophylactically effective quantity of virus-specific immune cells comprising a CAR or nucleic acid encoding a CAR comprising:
i) an antigen binding domain that specifically binds CD30,
ii) a transmembrane domain,
iii) a signaling domain comprising:
(a) an amino acid sequence derived from the intracellular domain of CD28
(b) an amino acid sequence comprising an immunoreceptor tyrosine-based activation motif (ITAM).
Independent claim 18 and dependent claims thereof are drawn to a method of killing alloreactive immune cells by contacting alloreactive immune cells with a virus-specific immune cell comprising a CAR or nucleic acid encoding a CAR for use in a method of treating or preventing a disease or condition characterized by an alloreactive immune response wherein the CAR comprises:
i) an antigen binding domain that specifically binds CD30,
ii) a transmembrane domain,
iii) a signaling domain comprising:
(a) an amino acid sequence derived from the intracellular domain of CD28
(b) an amino acid sequence comprising an immunoreceptor tyrosine-based activation motif (ITAM).
Dependent claims 19, 37, and 41 further limits the signaling domain to comprises an amino acid sequence that is at least 80% identical to SEQ ID NO:26, or the transmembrane domain derived from the transmembrane domain of CD28 that the at least 80% identical to SEQ ID NO:20, or the antigen binding domain comprises amino acid sequences that are at least 80% identical to SEQ ID NOs: 14 and 15, respectively.
The claims in the reference application are drawn to a composition comprising a virus-specific immune cells comprising a CAR or a nucleic acid encoding a CAR, wherein the CAR comprises a CD30 antigen-binding domain, a transmembrane domain, a signally domain comprising an amino acid sequence that is 80% identical to SQE ID NO:26 and an ITAM. Dependent claims, e.g. claim 5, further limit the CD30 antigen binding domain to have the amino acid sequences having at least 80% identity to SEQ ID NOs: 14, and 15, or the CAR having an amino acid sequence that is at least 80% identical to SEQ ID NO:35.
The claims in the reference application differ from the instant claims by not reciting a method of treating a disease characterized by an alloreactive immune response by administering the virus-specific immune cells.
The teachings of Savoldo et al. have been discussed above.
It would thus be obvious to one or ordinary skill in the art at the time the instant invention was filed to administer the composition recited in the reference application to treat CD30+ lymphomas. An ordinary skill in the art would have been motivated to do so, and have a reasonable expectation of success, since Savoldo et al. teach Epstein Barr virus-specific cytotoxic T lymphocytes expressing the anti-CD30 CAR for immunotherapy of Hodgekin’s disease. Therefore, administering the composition recited in the copending application comprising same virus-specific immune cells containing identical CD30 CAR T cells would be well within the skill of an ordinary artisan. As such, the claims in the reference application would render the instant claims obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
14. Claims 3, 4, 7, 12, 13, 17-19, 28, 35, 37, 38, 40-42, and 44 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 3-13, 15, 16, and 20-22 of copending USSN 17/997,154 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because both instant claims and the claims in the reference application are drawn to the same or nearly the same methods of treating a disease by administering the same or nearly the same virus-specific immune cells comprising the same or nearly the same CD30 CAR. As such, the species of method of treating a cancer recited in the reference application would anticipate the genus of the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
15. No claim is allowed.
16. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHUN DAHLE whose telephone number is (571)272-8142. The examiner can normally be reached Mon-Fri 6:30am-4:00pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHUN W DAHLE/Primary Examiner, Art Unit 1641