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 .
Claims 17-21 are pending.
Applicant’s election of Group III that read on (A) CD28 as the species of co-stimulatory molecule on the surface of T cells in the reply filed of June 25, 2026 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)).
Claims 17-21, drawn to a method of expanding a population of T cells expressing said CAR, are being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 61/888,259, filed Oct 8, 2013, is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on June 25, 2026 and May 6, 2024 have been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
Drawings
The drawings filed on August 17, 2023 are acceptable.
Specification
The amendment to the specification filed on August 24, 2024 has been entered.
Applicants should amend the first line of the specification to update the relationship between the instant application and U.S. Application No. 16/365,588, filed March 26, 2019, now abandoned.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim rejections under - 35 U.S.C. 112
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.
Claims 17-21 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The Written Description Guidelines for examination of patent applications indicates, “the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical characteristics and/or other chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show applicant was in possession of the claimed genus.” (see MPEP 2163).
Claim 17 encompasses a method of expanding a population of T cells, comprising contacting the population of T cells with: a) any agent capable of stimulating a CD3 TCR complex; and
b) an agent capable of stimulating a co-stimulatory molecule on the surface of T cells,
wherein the T cells are genetically modified to express a CD 19-specific chimeric antigen receptor (CAR), and wherein the CAR comprises, in order from N-terminus to C- terminus:
the amino acid sequence of SEQ ID NO: 7;
ii) the amino acid sequence of SEQ ID NO: 13;
iii) the amino acid sequence of SEQ ID NO: 11; and
iv) the amino acid sequence of SEQ ID NO: 10.
Claim 18 encompasses the method of claim 17, wherein the agent capable of stimulating any CD3 TCR complex comprises an anti-CD3 antibody.
Claim 19 encompasses the method of claim 17, wherein the co-stimulatory molecule on the surface of T cells is selected from the group consisting of CD27, CD28, 4-1BB, OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, and CD83.
Claim 20 encompasses the method of claim 17, wherein the agent capable of stimulating a co-stimulatory molecule on the surface of T cells comprises any anti-CD28 antibody.
Claim 21 encompasses the method of claim 17, wherein the population of T cells are contacted with any anti-CD3 antibody and any anti-CD28 antibody.
The specification discloses:
[0045] Generally, the T cells of the invention are expanded by contact with an agent that stimulates a CD3 TCR complex and a co-stimulatory molecule on the surface of the T cells to create an activation signal for the T-cell.
[0046] For example, chemicals such as calcium ionophore A23187, phorbol 12-myristate 13-acetate (PMA), or mitogenic lectins like phytohemagglutinin (PHA) can be used to create an activation signal for the T-cell.
[0047] As non limiting examples, T cell populations may be stimulated in vitro such as by contact with an anti-CD3 antibody, or antigen-binding fragment thereof, or an anti-CD2 antibody immobilized on a surface, or by contact with a protein kinase C activator (e.g., bryostatin) in conjunction with a calcium ionophore. For co-stimulation of an accessory molecule on the surface of the T cells, a ligand that binds the accessory molecule is used. For example, a population of T cells can be contacted with ananti-CD3 antibody and an anti-CD28 antibody, under conditions appropriate for stimulating proliferation of the T cells. Conditions appropriate for T cell culture include an appropriate media (e.g., Minimal Essential Media or RPMI Media 1640 or, X-vivo 5, (Lonza)) that may contain factors necessary for proliferation and viability, including serum (e.g., fetal bovine or human serum), interleukin-2 (IL-2), insulin, IFN-g, IL-4, IL-7, GM-CSF, -10, -2, IL-15, TGFb, and TNF- or any other additives for the growth of cells known to the skilled artisan.
However, the specification does not describe the structures for the broad genus of “agent” capable of stimulating any CD3 TCR complex and “agent” capable of stimulating any co-stimulatory molecule on the surface of T cells (claim 17) encompassed by the claimed method.
The specification does not disclose a representative number of species of agents nor provides a structure-function relationship sufficient to enable a person of ordinary skill in the art to ‘visualize or recognize’ the members of the germs of agents capable of stimulating any CD3 TCR complex and agents capable of stimulating any co-stimulatory molecule on the surface of T cells at the time of filing.
Even assuming the co-stimulatory molecule on the surface of T cells is CD28 (elected species), (claim 19), the specification does not describe the structure, e.g., amino acid sequence of heavy and light chain variable region that bind to any agent, e.g., antibodies that bind to CD28 (elected species), much less for CD27, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, or CD83 encompassed by the claimed method.
It is known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. (of record) taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 22:159-168, 2009; see, e.g., Discussion).
Similarly, Edwards et al., (J Mol Biol. 334(1): 103-118, 2003; PTO 892), found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Poosarla et al (Biotechn. Bioeng 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Dufner (Trends Biotechnol. 24(11):523-529, 2006; PTO 892) teaches: “specific structural information - on the antibody to be optimized, its antigen and their interaction- is rarely available or lacks the high resolution required to determine accurately important details such as side-chain conformations, hydrogen-bonding patterns and the position of water molecules (p. 527, Col. 2, 1). Thus, a skilled artisan cannot, as one can do with a fully described genus of agents, visualize or recognize the identity of the members of the genus that exhibit this functional property, e.g., stimulating any CD3 TCR complex and stimulating any co-stimulatory molecule on the surface of T cells.
“For genus claims using functional language, … the written description ‘must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.” Id (quoting Araid Pharms., 598 F.3d at 1349).
A “representative number of species” means any such number of species that adequately describes the entire genus. Thus, when there is a substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Jansen Biotech, Inc., 759 F.3d 1285, 1300 (Fed. Cir. 2014). Satisfactory disclosure of a “representative number” depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. See MPEP §2163 (9th ed. Rev. 07-2022 Feb. 2023).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (see page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (see Vas-Cath at page 1116).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
When there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. A description of what a material does, rather than of what it is, usually does not suffice. Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. The Federal Circuit has held that “a sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the germs so that one of skill in the art can "visualize or recognize" the members of the genus" (Id. at 1.350, quoting Regents of the University of California v. Eli Lilly, 119 F.3d 1559, 1568-69 (Fed. Cir. 1997)).
As such, it appears that the instant specification does not adequately disclose the breadth of agents that stimulate CD3 TCR complex and any co-stimulatory molecule such as the ones in recited in claim 19, including, any anti-CD3 antibody and/or any anti-CD28 antibody encompassed by the claimed method. A skilled artisan would reasonably conclude that Applicant was not in possession of the genus of all the said agents, anti-CD3 antibody, and/or anti-CD28 antibody at the time the instant application was filed.
Therefore, only a method of expanding a population of T cells, comprising contacting the population of T cells with:
a) any agent capable of stimulating a CD3 TCR complex; and
b) an agent capable of stimulating a co-stimulatory molecule on the surface of T cells,
wherein the T cells are genetically modified to express a CD19-specific chimeric antigen receptor (CAR), and wherein the CAR comprises, in order from N-terminus to C- terminus:
the amino acid sequence of SEQ ID NO: 7;
ii) the amino acid sequence of SEQ ID NO: 13;
iii) the amino acid sequence of SEQ ID NO: 11; and
iv) the amino acid sequence of SEQ ID NO: 10,
wherein the agent capable of stimulating a co-stimulatory molecule on the surface of T cells comprises an anti-CD3 antibody and
wherein the agent capable of stimulating a co-stimulatory molecule on the surface of T cells comprises an anti-CD28 antibody, but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 17-21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 10,874,693. Although the claims at issue are not identical, they are not patentably distinct from each other because while the ‘693 patent issued from the application which served as the grandparent for the present case, the examined application was filed as a CON, not a DIV, and therefore no shield against double patenting that might be provided by 35 U.S.C 121 would be applicable here.
Issued claim 1 recites a CD19 specific chimeric antigen receptor (CAR), wherein the CAR comprises the amino acid sequence of SEQ ID NO: 15, which comprises the claimed SEQ ID NO: 7, 13, 11 and 10, see sequence alignment below, SEQ ID NO: 13 in bold, SEQ ID NO: 11 in italic.
ALIGNMENT:
Query Match 100.0%; Score 2534; Length 495;
Best Local Similarity 100.0%;
Matches 475; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLQQSGPELIKPGASVKMSCKASGYTFTSYVMHWVKQKPGQGLEWIGYINPYNDGTKY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 21 EVQLQQSGPELIKPGASVKMSCKASGYTFTSYVMHWVKQKPGQGLEWIGYINPYNDGTKY 80
Qy 61 NEKFKGKATLTSDKSSSTAYMELSSLTSEDSAVYYCARGTYYYGSRVFDYWGQGTTLTVS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 81 NEKFKGKATLTSDKSSSTAYMELSSLTSEDSAVYYCARGTYYYGSRVFDYWGQGTTLTVS 140
Qy 121 SGGGGSGGGGSGGGGSDIVMTQAAPSIPVTPGESVSISCRSSKSLLNSNGNTYLYWFLQR 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 141 SGGGGSGGGGSGGGGSDIVMTQAAPSIPVTPGESVSISCRSSKSLLNSNGNTYLYWFLQR 200
Qy 181 PGQSPQLLIYRMSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHLEYPFTFG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 201 PGQSPQLLIYRMSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHLEYPFTFG 260
Qy 241 AGTKLELKRSDPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYI 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 261 AGTKLELKRSDPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYI 320
Qy 301 WAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGG 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 321 WAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGG 380
Qy 361 CELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEG 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 381 CELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEG 440
Qy 421 LYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 475
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 441 LYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR 495
2. The CD19 specific CAR of claim 1, wherein the CAR is bispecific.
3. The CD19 specific CAR of claim 1, wherein the CAR is expressed on the surface of a T-cell as part of an allogeneic immunotherapy treatment for cancer expressing CD19.
4. A polynucleotide encoding the CD19 specific CAR of claim 1.
5. An expression vector comprising the polynucleotide of claim 4.
6. An isolated T cell expressing the CD19 specific CAR of claim 1, wherein said T cell is a cytotoxic T lymphocyte (CTL).
7. A method of engineering an immune cell to express the CD19 specific CAR of claim 1, said method comprising introducing into an immune cell a polynucleotide encoding said CAR.
8. The method of claim 7, wherein said immune cell is a CTL.
9. A method of treating cancer in a subject, said method comprising administering to a subject having cancer expressing CD19 the T cell of claim 6.
10. The method of claim 9, wherein said cancer is a B-cell lymphoma or leukemia.
11. The method of claim 9, wherein said T cell administered to the subject is an allogeneic T cell.
A person of skill in the art, reading the claims of the ‘693 patent, would look to the patent and follow the ‘693 patent’s express instruction on how to expanding the population of T cells comprising the claimed CD19-specific antigen receptor (CAR) within the patent, e.g., an anti-CD3 antibody and an anti-CD28 antibody can expanded the population of T cells in vitro thereby arriving at the method of the examined claims.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
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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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641
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