DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claim listing filed October 27, 2025 is pending.
Claims 15-28 are canceled.
Claims 1-14 are pending.
Claim 1 is an independent claim.
Applicant’s election without traverse of Group I (claims 1-7, drawn to a chimeric antigen receptor); and the species of an intracellular domain comprising a CD3ε intracellular region with a Y/F mutation, a costimulatory signaling region, and a CD3𝞯 intracellular segment that are sequentially connected; wherein the CD3ε intracellular region is the immunoreceptor tyrosine-based activation motif and the costimulatory signaling region is an intracellular segment of CD28; an antigen recognition region is an anti-CD19 single-chain antibody; a transmembrane domain is a transmembrane region of CD28; and a hinge region is CD28 hinge region in the reply filed October 27, 2025.
It is noted that the Examiner erroneously withdrew claims 13 and 14 from consideration as being drawn to non-statutory subject matter. Claims 13 and 14 are rejoined with Group I.
The Applicant argues D1 does not disclose the following technical feature in claim 1 of this Application: a CD3ε intracellular region with a Y/F mutation, wherein two tyrosines in the immunoreceptor tyrosine-based activation motif of the CD3ε intracellular region are mutated into phenylalanine.
The Applicant also argues that the above disclosure in D1 is presented only as a broad, generic statement without any experimental validation. The Applicant asserts that specifically, in Example 2, D1 provides only three CARs respectively containing a portion of CD3ε (corresponds to CD3ε PRSITAM), all CD3ε positioned before the CD3𝞯 domain, and all CD3ε positioned after the CD3𝞯 domain, which are shown in FIG. 4a of D1 (see FIG. 1 below). The Applicant asserts that D1 further compares theses three CARs containing part or all of CD3ε with a CAR lacking CD3ε, and concludes that CARs containing CD3ε PRSITAM exhibit greater proliferation, improved antigen sensitivity, and enhanced in vivo antitumor function. The Applicant asserts that obviously, D1 provides no experimental data for CARs containing CD3ε BRS. The Applicant asserts that thus, a person skilled in the art would not have been able to predict the technical effect of incorporating CD3ε BRS into CARs. The Applicant asserts that besides, in light of D1, a skilled person would have been more inclined to choose CD3ε PRS_ITAM rather than CD3ε.
The Applicant further argues that additionally, D1 is mainly directed to augmenting CAR recognition of low-density antigens. The Applicant asserts that while D1 mentions that 4-1BB/CD3ε PRS_ITAM/ CD3𝞯 T cells exhibited greater proliferation, it does not investigate cell viability or apoptosis levels of CAR-T cells. The Applicant asserts that it is well understood by those skilled in the art that when the proliferation rate of CAR-T cells is lower than the apoptosis rate, overall viability still remains poor. The Applicant asserts that thus, D1 does not provide guidance on how to improve the viability, decrease the apoptosis level, and increase the proliferation ability of CAR-T simultaneously. The Applicant asserts that by contrast, the Background of this Application identifies a well-recognized problem in the art: CAR-T cells with traditional CARS (e.g., 28Z CAR-T cells) demonstrate limited continuous proliferation and poor viability, leading to unsatisfactory therapeutic outcomes. The Applicant asserts that this Application addresses this problem by providing CARS designed to improve viability, decrease apoptosis, and enhance proliferation of CAR-T cells, thereby increasing persistence and improving anti-tumor efficacy. The Applicant asserts that comparative experiments were conducted between the CARS of claim 1 of this Application and traditional CARs (28Z CAR-T cells as controls). The Applicant asserts that as shown in Examples 1 and 2, CAR-T cells with the claimed CARs exhibit superior viability, reduced apoptosis, robust proliferation, potent cytotoxicity against tumor cells, and enhanced antitumor activity. The Applicant asserts that therefore, the observed combination of high proliferation with low apoptosis in this Application could not have been expected. The Applicant asserts that according to the description above, since D1 provides no experimental data regarding CARs containing CD3ε BRS or CARS containing CD3ε ITAM with Y/F mutations, a person skilled in the art could not reasonably predict that such CARS would demonstrate the favorable viability.
The Applicant ultimately argues that in summary, the technical solution of claim 1 of the present Application achieves unexpected technical effects and therefore possesses an inventive step. The Applicant asserts that naturally, it can be concluded that claim 1 encompasses the special technical features of: (1) a CD3ε intracellular region with a Y/F mutation, wherein two tyrosines in the immunoreceptor tyrosine-based activation motif of the CD3ε intracellular region are mutated into phenylalanine; and (2) a CD3ε intracellular basic residue rich sequence.
Contrary to the Applicant’s arguments that (1) D1 does not disclose a CAR comprising a CD3ε intracellular region with a Y/F mutation, wherein two tyrosines in the immunoreceptor tyrosine-based activation motif of the CD3ε intracellular region are mutated into phenylalanine and (2) that claim 1 encompasses the special technical features of a CAR comprising a CD3ε intracellular region with a Y/F mutation, wherein two tyrosines in the immunoreceptor tyrosine-based activation motif of the CD3ε intracellular region are mutated into phenylalanine and a CD3ε intracellular basic residue rich sequence; note that that instant claim 1 is drawn to a CAR that comprises a CD3ε intracellular region with a Y/F mutation, wherein two tyrosines in the immunoreceptor tyrosine-based activation motif of the CD3ε intracellular region are mutated into phenylalanine or a CD3ε intracellular basic residue rich sequence. Therefore, in order for claim 1 to lack unity of invention the art only needs to teach a CAR with a CD3ε intracellular region comprising a Y/F mutation or BRS, but it does not need to teach that the CAR comprises both. Therefore, while the Examiner agrees that D1 does not disclose a CD3ε intracellular region with a Y/F mutation, wherein two tyrosines in the immunoreceptor tyrosine-based activation motif of the CD3ε intracellular region are mutated into phenylalanine, it is noted that D1 does not need to teach this feature when claim 1 is given the broadest reasonable interpretation.
Regarding the Applicant’s arguments that (1) D1 is presented only as a broad, generic statement without any experimental validation, (2) D1 provides no experimental data for CARs containing CD3ε BRS, (3) a person skilled in the art would not have been able to predict the technical effect of incorporating CD3ε BRS into CARs, and (4) a skilled person would have been more inclined to choose CD3ε PRS_ITAM rather than CD3ε; note that D1 only needs to disclose the instant invention in order to break unity but it does not need to provide proof (experimental data) that said invention works or is superior. A skilled artisan would not need to predict the technical effect of incorporating CD3ε BRS into CARs since D1 already teaches a CAR comprising a CD3ε BRS. In response to the Applicant’s argument that a skilled person would have been more inclined to choose CD3ε PRS_ITAM rather than CD3ε, the same logic applies. All that is required for D1 to anticipate the instant invention, and therefore break unity, is that it must teach every element required by the claim under its broadest reasonable interpretation. See MPEP 2131. Therefore, D1 only needs to disclose a CAR comprising a CD3ε BRS but does not need to provide evidence of why a CAR comprising a CD3ε BRS would work or why it would be the best choice.
Regarding the Applicant’s arguments that (1) D1 does not provide guidance on how to improve the viability, decrease the apoptosis level, and increase the proliferation ability of CAR-T simultaneously; (2) Examples 1 and 2, CAR-T cells with the claimed CARs exhibit superior viability, reduced apoptosis, robust proliferation, potent cytotoxicity against tumor cells, and enhanced antitumor activity, (3) the observed combination of high proliferation with low apoptosis in this Application could not have been expected, (4) D1 provides no experimental data regarding CARs containing CD3ε BRS or CARS containing CD3ε ITAM with Y/F mutations, a person skilled in the art could not reasonably predict that such CARS would demonstrate the favorable viability, and (5) the technical solution of claim 1 of the present Application achieves unexpected technical effects and therefore possesses an inventive step; it is noted that similarly to the arguments above, D1 only needs to disclose the instant invention in order to break unity but it does not need to provide proof (experimental data) that said invention works or is superior. A skilled artisan would not need to predict the improved viability, decreased apoptosis level, and increases proliferation ability of CAR-T simultaneously as asserted by the Applicant. All that is required for D1 to anticipate the instant invention, and therefore break unity, is that it must teach every element required by the claim under its broadest reasonable interpretation. See MPEP 2131. Therefore, D1 only needs to disclose a CAR comprising a CD3ε BRS but does not need to provide evidence of why a CAR comprising a CD3ε BRS would work or why it would be the best choice.
Therefore, the restriction requirement mailed 08/26/2025 is still deemed proper and is therefore maintained.
Claims 8-12 have been withdrawn from further consideration pursuant to 37 CFR
1.142(b) as being drawn to nonelected inventions.
Claims 1-7, 13, and 14 are currently under consideration.
Priority
The instant application is a 371 of PCT/CN2021/099798 filed 06/11/2021 and claims foreign priority to CN202010733636.2 filed 07/27/2020 and CN202010734872.6 filed 07/27/2020.
Certified translated copies of CN202010733636.2 and CN202010734872.6 have not been filed. Therefore, it is not clear if the foreign priority documents have adequate support for the instant claims.
Information Disclosure Statement
It is noted that the NPL references cited in the IDS filed 01/24/2023 have not been considered because the Applicant has not attached a copy of any of the references. It is noted that in addition to the list of information, each information disclosure statement must also include a legible copy of:
(A) Each foreign patent;
(B) Each publication or that portion which caused it to be listed , other than U.S. patents and U.S. patent application publications unless required by the Office;
(C) For each cited pending unpublished U.S. application, the application specification including the claims, and any drawings of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system. The requirement in 37 CFR 1.98(a)(2)(iii) for a legible copy of the specification, including the claims, and drawings of each cited pending U.S. patent application (or portion of the application which caused it to be listed) is sua sponte waived where the cited pending application is stored in the USPTO’s IFW system. See Waiver of the Copy Requirement in 37 CFR 1.98 for Cited Pending U.S. Patent Applications, 1287 OG 163 (October 19, 2004); and
(D) All other information or that portion which caused it to be listed.
See MPEP 609.04(a).II.
Nucleotide and/or Amino Acid Sequence Disclosures
The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete. The incorporation by reference paragraph in the amendments to the specification filed February 22, 2023 recites the file size in “Kb” when it should be in “bytes” (i.e. 26,787 bytes) and recites the incorrect file name and date of creation. The name should be “sequence_220881_ST25.txt” and the date of creation should be “December 23, 2025.”
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 incorporation by reference paragraph, 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.
Claim Objections
Claims 1-7, 13, and 14 are objected to because of the following informalities:
Claim 1 recites “A chimeric antigen receptor, comprises” where it should recite “A chimeric antigen receptor comprising” in line 1.
Claim 1 also recites:
“one end of the intracellular domain which is connected to the transmembrane domain is connected to a CD3 intracellular region with a Y/F mutation, wherein two tyrosines in the immunoreceptor tyrosine-based activation motif of CD3ε intracellular region with a Y/F mutation are mutated into phenylalanine; or one end of the intracellular domain which is connected to the transmembrane domain is connected to a CD3ε intracellular basic residue rich sequence” where it should recite:
“one end of the intracellular domain, which is connected to the transmembrane domain, comprises a CD3 intracellular region with a Y/F mutation, wherein two tyrosines in the immunoreceptor tyrosine-based activation motif of the CD3ε intracellular region with a Y/F mutation are mutated into phenylalanine; or one end of the intracellular domain, which is connected to the transmembrane domain, comprises a CD3ε intracellular basic residue rich sequence” in lines 6-10.
Claim 2 recites:
“The chimeric antigen receptor according to claim 1, further comprises one or more of the following: (1) the amino acid sequence of the CD3ε intracellular region with a Y/F mutation is shown as SEQ ID NO: 1; (2) the intracellular domain comprises the CD3 intracellular region with a Y/F mutation, a costimulatory signaling region, and a CD3𝞯 intracellular segment that are sequentially connected; (3) the amino acid sequence of the CD3ε intracellular basic residue rich sequence is shown as SEQ ID NO: 10; (4) the intracellular domain comprises the CD3ε intracellular basic residue rich sequence, the costimulatory signaling region, and the CD3𝞯 intracellular segment that are sequentially connected” where it should recite:
“The chimeric antigen receptor according to claim 1, wherein: (1) the amino acid sequence of the CD3ε intracellular region with the Y/F mutation is SEQ ID NO: 1; and/or (2) the intracellular domain comprising the CD3 intracellular region with the Y/F mutation further comprises a costimulatory signaling region and a CD3𝞯 intracellular segment that are sequentially connected; or (3) the amino acid sequence of the CD3ε intracellular basic residue rich sequence is SEQ ID NO: 10; and/or (4) the intracellular domain comprising the CD3ε intracellular basic residue rich sequence further comprises a costimulatory signaling region and a CD3𝞯 intracellular segment that are sequentially connected.”
Claim 3 recites “wherein the costimulatory signaling region is selected from one or more of intracellular segments of CD27, CD28, CD134, 4-1BB, OX40, and ICOS” in lines 1-3. It is noted that CD134 and OX40 are synonymous. The Applicant is advised to delete one of CD134 or OX40 otherwise the claim is redundant.
Claims 4, 6, and 7 recites “is shown as SEQ ID NO:” where it should recite “is SEQ ID NO:” in several lines.
Claims 4-7 also recite “The chimeric antigen receptor according to claim X, further comprises one or more of the following” where it should recite “The chimeric antigen receptor according to claim X, wherein” in lines 1 and 2.
Claim 4 also recites “SEQ ID NO:2; (2) the amino acid sequence of the CD3𝞯 intracellular segment is” where it should recite “SEQ ID NO:2; and (2) the amino acid sequence of the CD3𝞯 intracellular segment is” in lines 3 and 4.
Claim 5 also recites:
“b. the transmembrane domain is selected from one or more of transmembrane regions of CD28, CD4, CD8a, OX40, and H2-Kb;c. the hinge region is selected from one or more of CD28 hinge region, CD8a hinge region, CD4 hinge region, IgG hinge region, or a coupled hinge region of IgG hinge region and CH2CH3 region” where it should recite:
“b. the transmembrane domain is selected from one or more of the transmembrane regions of CD28, CD4, CD8a, OX40, and H2-Kb; and/or c. the hinge region is selected from one or more of a CD28 hinge region, CD8a hinge region, CD4 hinge region, IgG hinge region, coupled hinge region of IgG hinge region, and CH2CH3 region” in lines 7-10.
Claim 6 also recites “SEQ ID NO:4; f. the amino acid sequence of the CD28 hinge region is” where it should recite “SEQ ID NO:4; and/or f. the amino acid sequence of the CD28 hinge region” in lines 3 and 4.
Claim 7 also recites:
“1) the antigen recognition region of the chimeric antigen receptor containing the CD3a intracellular region with a Y/F mutation is selected from FMC63, the hinge region is selected from the CD28 hinge region, the transmembrane domain is selected from the CD28 transmembrane region, and the intracellular domain includes the CD3ε intracellular region with a Y/F mutation, the CD28 intracellular segment, and the CD3𝞯 intracellular segment that are sequentially connected;” where it should recite:
“1) the antigen recognition region of the chimeric antigen receptor containing the CD3a intracellular region with the Y/F mutation is FMC63, the hinge region is a CD28 hinge region, the transmembrane domain a CD28 transmembrane region, and the intracellular domain includes the CD3ε intracellular region with the Y/F mutation, the CD28 intracellular segment, and the CD3𝞯 intracellular segment that are sequentially connected; and/or” in lines 3-7.
Claim 7 also recites:
“2) the amino acid sequence of the chimeric antigen receptor containing the CD3Ε intracellular region with a Y/F mutation is shown as SEQ ID NO:5;” where it should recite:
“2) the amino acid sequence of the chimeric antigen receptor containing the CD3Ε intracellular region with the Y/F mutation is SEQ ID NO:5; or” in lines 8 and 9.
Claim 7 also recites:
“3) the antigen recognition region of the chimeric antigen receptor containing the CD3Ε intracellular basic residue rich sequence is selected from FMC63, the hinge region is selected from CD28 hinge region, the transmembrane domain is selected from CD28 transmembrane region, and the intracellular domain includes the CD3Ε intracellular basic residue rich sequence, the CD28 intracellular segment, and the CD3𝞯 intracellular segment that are sequentially connected;” where it should recite:
“3) the antigen recognition region of the chimeric antigen receptor containing the CD3Ε intracellular basic residue rich sequence is FMC63, the hinge region is a CD28 hinge region, the transmembrane domain is a CD28 transmembrane region, and the intracellular domain includes the CD3Ε intracellular basic residue rich sequence, the CD28 intracellular segment, and the CD3𝞯 intracellular segment that are sequentially connected; and/or” in lines 10-14.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 13 and 14 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claims do not fall within at least one of the four categories of patent eligible subject matter because claims 13 and 14 are directed to the “use” of a chimeric antigen receptor.
"Use" claims are non-statutory under 35 U.S.C. 101 because the claimed recitation of a use, without setting forth any steps involved in the process, results in an improper definition of a process, i.e., results in a claim which is not a proper process claim under 35 U.S.C. 101. See for example Ex parte Dunki , 153 USPQ 678 (Bd. App. 1967) and Clinical Products, Ltd v. Brenner, 255 F. Supp. 131, 149 USPQ 475 (D.D.C. 1966). See MPEP 2173.05(q).
Canceling claims 13 and 14 or amending claims 13 and 14 to be directed to statutory subject matter would obviate this part of the rejection.
For the purpose of applying prior art, claims 13 and 14 are being read as the CAR of claim 1.
Claim Rejections - 35 USC § 112
Indefinite language
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 1-7, 13, and 14 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 “and one end of the intracellular domain which is connected to the transmembrane domain is connected to a CD3 intracellular region with a Y/F mutation, wherein two tyrosines in the immunoreceptor tyrosine-based activation motif of CD3ε intracellular region with a Y/F mutation are mutated into phenylalanine” in lines 6-10. The recitation of “two tyrosines” being mutated in line 7 lacks antecedent basis because the prior recitation “a Y/F mutation” in line 6 means that there is only one Y-to-F mutation not two. The recitation of a singular Y-to-F mutation followed by plural Y-to-F mutations renders the claim indefinite because it is unclear how many Y-to-F mutations the CAR should comprise.
Amending claim 1 to recite “and one end of the intracellular domain which is connected to the transmembrane domain is connected to a CD3 intracellular region with two Y/F mutations, wherein two tyrosines in the immunoreceptor tyrosine-based activation motif of CD3ε intracellular region are mutated into phenylalanine” would obviate this part of the rejection.
Claim 3 recites “wherein the costimulatory signaling region is selected from one or more of intracellular segments of CD27, CD28, CD 134, 4-1BB, OX40, and ICOS” in lines 1-3. However, claim 3 is dependent on claim 2. When given the broadest reasonable interpretation, claim 2 is drawn to a CAR that may or may not comprise a co-stimulatory signaling region. Therefore, in the case that claim 2 is drawn to a CAR without a costimulatory signaling region, the limitation of “the costimulatory signaling region” in lines 1 and 2 of claim 3 lacks antecedent basis.
Furthermore, in the case that claim 2 is drawn to a CAR with a costimulatory signaling region, the recitation of “a” and “the” proceeding the term “costimulatory signaling region” in claims 2 and 3 means that there is only one costimulatory signaling region. However the recitation of “one or more of” in line 2 of claim 3 means that there can be more than one costimulatory signaling region. The recitation of a singular costimulatory signaling region followed by plural costimulatory signaling regions renders the claim indefinite because it is unclear how many costimulatory signaling regions the CAR should comprise.
Amending claim 3 to recite “wherein the intracellular domain further comprises a costimulatory signaling region wherein the costimulatory signaling region is selected from an intracellular segment of CD27, CD28, CD 134, 4-1BB, OX40, or ICOS” in lines 1-3 would obviate this part of the rejection.
Claim 5 recites “a. the antigen recognition region is selected from a single-chain antibody against a tumor surface antigen, and the tumor surface antigen is selected from one or more of CD 19, mesothelin, CD20, CD22, CD123, CD30, CD33, CD38, CD138, BCMA, Fibroblast activation protein, Glypican-3, CEA, EGFRvIII, PSMA, Her2, IL13Ra2, CD171, and GD2; b. the transmembrane domain is selected from one or more of transmembrane regions of CD28, CD4, CD8a, OX40, and H2-Kb; c. the hinge region is selected from one or more of CD28 hinge region, CD8a hinge region, CD4 hinge region, IgG hinge region, or a coupled hinge region of IgG hinge region and CH2CH3 region” in lines 3-10. However, claim 5 is dependent on claim 1 which recites “an extracellular domain, a transmembrane domain, and an intracellular domain” in line 2.
The recitation of “a,” “an,” and “the” proceeding the terms “antigen recognition region,” “tumor surface antigen,” “transmembrane domain,” and “hinge region” in claims 1 and 5 means that there is only one antigen recognition region, tumor surface antigen, transmembrane domain, and hinge region. However the recitation of “one or more of” in lines 4, 7, and 9 of claim 5 means that there can be more than one antigen recognition region, tumor surface antigen, transmembrane domain, and hinge region. The recitation of a singular antigen recognition region, tumor surface antigen, transmembrane domain, and hinge region followed by plural antigen recognition regions, tumor surface antigens, transmembrane domains, and hinge regions renders the claim indefinite because it is unclear how many antigen recognition regions, tumor surface antigens, transmembrane domains, and hinge regions the CAR should comprise.
Amending claim 5 to recite “a. the antigen recognition region is selected from a single-chain antibody against a tumor surface antigen, and the tumor surface antigen is CD 19, mesothelin, CD20, CD22, CD123, CD30, CD33, CD38, CD138, BCMA, Fibroblast activation protein, Glypican-3, CEA, EGFRvIII, PSMA, Her2, IL13Ra2, CD171, or GD2; b. the transmembrane domain is a transmembrane region of CD28, CD4, CD8a, OX40, or H2-Kb; c. the hinge region is a CD28 hinge region, CD8a hinge region, CD4 hinge region, IgG hinge region, a coupled hinge region of IgG hinge region, or CH2CH3 hinge region” in lines 3-10 would obviate this part of the rejection.
Claim 7 recites “the CD28 intracellular segment” in lines 6 and 13 and “the CD3𝞯 intracellular segment” in lines 7 and 14. However, claim 7 is dependent on claims 1, 5, and 6 which do not recite a CD28 intracellular segment or a CD3𝞯 intracellular segment. Therefore, these limitations lack antecedent basis.
Amending claim 7 to recite “a CD28 intracellular segment” and “a CD3𝞯 intracellular segment” would obviate this part of the rejection.
Claims 13 and 14 are directed to the “use” of a chimeric antigen receptor. Attempts to claim a process without setting forth any steps involved in the process generally raises an issue of indefiniteness under 35 U.S.C. 112(b). For example, a claim which read: "[a] process for using monoclonal antibodies of claim 4 to isolate and purify human fibroblast interferon" was held to be indefinite because it merely recites a use without any active, positive steps delimiting how this use is actually practiced. Ex parte Erlich, 3 USPQ2d 1011 (Bd. Pat. App. & Inter. 1986). See MPEP 2173.05(q).
This applies to the instant case where claims 13 and 14 claim “use of the chimeric antigen receptor” without reciting any steps involved in said use.
Canceling claims 13 and 14 or amending claims 13 and 14 to recites “A method for…” would obviate this part of the rejection.
Written Description
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 1-7, 13, and 14 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 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.
The instant claims are drawn to a genus of chimeric antigen receptors comprising an extracellular domain, a transmembrane domain, and an intracellular domain which are connected in sequence; wherein the extracellular domain comprises an antigen recognition region and a hinge region; and one end of the intracellular domain, which is connected to the transmembrane domain, is connected to a CD3ε intracellular region with a Y/F mutation, wherein two tyrosines in the immunoreceptor tyrosine-based activation motif of CD3ε intracellular region with a Y/F mutation are mutated into phenylalanine; or one end of the intracellular domain, which is connected to the transmembrane domain, is connected to a CD3ε intracellular basic residue rich sequence.
Claims 5-7 are drawn to a subgenus of chimeric antigen receptors wherein the antigen recognition region is a single-chain antibody against a tumor surface antigen, and wherein the tumor surface antigen is CD19, mesothelin, CD20, CD22, CD123, CD30, CD33, CD38, CD138, BCMA, Fibroblast activation protein, Glypican-3, CEA, EGFRvIII, PSMA, Her2, IL13Ra2, CD171, or GD2.
Regarding the CD3ε intracellular region, the Applicant has disclosed three CD3ε intracellular regions all of which comprise a basic residue rich sequence (BRS) (e.g. see Figures 1a and 2a). It is noted that the CD3ε intracellular region of Figure 2a only comprises a BRS while the CD3ε intracellular regions of Figure 1a further comprises an immunoreceptor tyrosine-based activation motif (ITAM) and a proline rich sequence (PRS) (e.g. see Figure 1a, SEQ ID NOs: 1 and 14 which are copied and annotated below). It is noted that SEQ ID NO: 14 comprises a wildtype ITAM and SEQ ID NO: 1 comprises a mutant ITAM comprising two Tyr-to-Phe point mutations.
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Regarding the anti-tumor surface antigen single-chain antibody, the Applicant has only disclosed the anti-CD19 single-chain antibody FMC63 (e.g. see [00169]).
The Applicant has disclosed several working examples that apply CARs comprising no CD3ε intracellular region (28Z), a wildtype CD3ε intracellular region (E28Z), a double Y/F mutant CD3ε intracellular region (EYF28Z), or a truncated CD3ε intracellular region comprising only the BRS (EBRS28Z) (e.g. see embodiments 1 and 2).
The anti-CD19 28Z CAR sequence includes FMC63 single-chain antibody, CD28 hinge region, CD28 transmembrane region, CD28 and CD3𝞯 intracellular region structure, which is shared by Rosenberg, S.A. laboratory on the NCBI (GenBank: HM852952.1) (e.g. see [00169]).
For the anti-CD19 EYF28Z CAR (encoded by SEQ ID NO: 8), an CD3ε intracellular region with a Y/F mutation (both tyrosines in the ITAM of the intracellular region are mutated to phenylalanines) was inserted behind the CD28 transmembrane region of the anti-CD19 28Z CAR sequence (e.g. see [00169]). For the anti-CD19 E28Z CAR (encoded by SEQ ID NO: 9), the CD3ε intracellular region with a Y/F mutation of the anti-CD19 EYF28Z CAR is replaced by a wildtype CD3ε intracellular region (e.g. see [00172).
For the anti-CD19 EBRS28Z CAR (encoded by SEQ ID NO: 13), a BRS motif of the CD3ε intracellular segment was inserted behind the CD28 transmembrane region of the anti-CD19 28Z CAR sequence (e.g. see [00201]). It is noted that anti-CD19 EBRS28Z CAR only comprises the BRS of the CD3ε intracellular segment and does not comprise the ITAM or the PRS, see sequence alignment of the anti-CD19 EBRS28Z CAR (Qy) and the anti-CD19 EYF28Z CAR (Db) below. The amino acid sequences were obtained by translating the nucleic acid sequences SEQ ID NOs: 13 and 8, respectively.
The Applicant discloses that the anti-CD19 EYF28Z CAR-T cells produced significantly more IL-2, IFN-y, and TNF-α than anti-CD19 E28Z CAR-T cells after being specifically stimulated by CD19+ cells (e.g. see [00179]). The Applicant also discloses that the anti-CD19 EBRS28Z CAR-T cells produced similar amounts of IL-2 and TNF-α compared anti-CD19 28Z CAR-T cells after being specifically stimulated by CD19+ cells, while the amount of IFN-y was less than that of anti-CD19 28Z CAR-T cells (e.g. see [00209]). These results indicate that the ITAM of the CD3ε intracellular region has an important inhibitory effect on the production of cytokines (e.g. see [00179]). However, it is noteworthy that the cytokines IFN-y and TNF-α secreted by anti-CD19 EYF28Z CAR-T cells were still significantly less than those of anti-CD19 28Z CAR-T cells manifesting the anti-CD19 EYF28Z CAR-T cells can reduce the activation of macrophages and monocytes to produce inflammatory cytokines such as IL-1 ß and IL-6 (e.g. see [00179]).
The Applicant also discloses that anti-CD19 EYF28Z CAR-T cells and the anti-CD19 EBRS28Z CAR-T cells have stronger proliferation and viability than that of anti-CD19 28Z CAR-T cells after being stimulated by CD19+ cells (e.g. see [00180]-[00182], [00184], and [00210]-[00213]).
The Applicant also discloses that the cytotoxicity of the anti-CD19 EYF28Z CAR-T cells and the anti-CD19 EBRS28Z CAR-T cells against CD19+ tumor cells was similar to that of anti-CD19 28Z CAR-T cells (e.g. see and [00183] and [00214]).
The Applicant also discloses that anti-CD19 EYF28Z CAR-T cells have stronger proliferation and viability than and similar cytotoxicity to that of anti-CD19 E28Z CAR-T cells after being stimulated by CD19+ cells (e.g. see [00180]-[00183]).
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When given the broadest reasonable interpretation in light of specification, the CAR of the instant invention is defined broadly to be any CAR that comprises any CD3ε intracellular region with (a) a Y/F mutation, wherein two tyrosines in the immunoreceptor tyrosine-based activation motif of CD3ε intracellular region with a Y/F mutation are mutated into phenylalanine; or (b) any basic residue rich sequence.
Furthermore, regarding the subgenus of CARs comprising an anti-tumor surface antigen single-chain antibody as the antigen binding domain, when given the broadest reasonable interpretation in light of specification, the subgenus CARs of the instant invention is defined broadly to encompass any CAR that comprises any single-chain antibody that binds any of CD19, mesothelin, CD20, CD22, CD123, CD30, CD33, CD38, CD138, BCMA, Fibroblast activation protein, Glypican-3, CEA, EGFRvIII, PSMA, Her2, IL13Ra2, CD171, or GD2.
It is noted that no claim indicates sufficient structure for the genus of CARs comprising a CD3ε intracellular region. It is further noted that claim indicates sufficient structure for the subgenus CARs comprising a single-chain antibody that binds CD19, mesothelin, CD20, CD22, CD123, CD30, CD33, CD38, CD138, BCMA, Fibroblast activation protein, Glypican-3, CEA, EGFRvIII, PSMA, Her2, IL13Ra2, CD171, or GD2.
Regarding the genus of CARs comprising any CD3ε intracellular region with (a) a Y/F mutation, wherein two tyrosines in the immunoreceptor tyrosine-based activation motif of CD3ε intracellular region with a Y/F mutation are mutated into phenylalanine; or (b) any basic residue rich sequence, Bettini et al. 2014 (J Immunol. 193(1): 258–267) teach that CD3ε comprises an ITAM, a PRS, and a BRS (e.g. see paragraph spanning pages 258 and 259). Bettini et al. also teach that deletion of the CD3ε intracellular chains blocks early thymocyte development but mutating the CD3ε ITAM motifs does not affect T cell development, suggesting that there are additional critical motifs in the CD3ε cytoplasmic domain. Bettini et al. teach that the PRS , which recruits the adapter molecule Nck, facilitates early thymocyte development and enhances signals to low-avidity TCR:pMHC interactions. Bettini et al. also teach that a CD3ε membrane-proximal basic-rich stretch (BRS) was shown to be critical for plasma membrane binding by the CD3ε cytoplasmic tail (e.g. see paragraph spanning pages 258 and 259).
Bettini et al. ultimately teach that the BRS of CD3ε plays a critical physiological role in regulating TCR signaling, thereby facilitating optimal T cell development, peripheral T cell function and the generation of protective immunity (e.g. see page 259, left column, second paragraph). In fact, Bettini et al. teach that mutating only three of the six residues in this motif significantly impacted not only thymocyte differentiation but also subsequent TCR expression and signaling capacity (e.g. see paragraph spanning pages 265 and 266). Bettini et al. also teach that thymocytes expressing CD3ε-BRS mutations exhibited cell intrinsic defects and were at a competitive disadvantage compared with WT thymocytes (e.g. see paragraph spanning pages 265 and 266).
This the art ultimately teaches that in order to have a functional CD3ε intracellular signaling region that allows for proper regulation of TCR signaling, thereby facilitating optimal T cell development, peripheral T cell function and the generation of protective immunity, the CD3ε intracellular signaling region must comprise at least a wildtype full-length BRS. Furthermore, the ITAM of the CD3ε intracellular signaling region, including the PRS, does not seem to as critical for T-cell function an may be deleted or mutated.
This applies to the instant case where the instant invention is drawn to a genus of CARs comprising any CD3ε intracellular region with or without any basic residue rich sequence.
Regarding subgenus of CARs that comprise a single-chain antibody, an antibody fragment, that binds to CD19, mesothelin, CD20, CD22, CD123, CD30, CD33, CD38, CD138, BCMA, Fibroblast activation protein, Glypican-3, CEA, EGFRvIII, PSMA, Her2, IL13Ra2, CD171, or GD2, artisans are well aware that knowledge of a given antigen (for instance CD19, mesothelin, CD20, CD22, CD123, CD30, CD33, CD38, CD138, BCMA, Fibroblast activation protein, Glypican-3, CEA, EGFRvIII, PSMA, Her2, IL13Ra2, CD171, or GD2) 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).
As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen, as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data, such as that of Edwards et al., indicating the diversity of sequences in a population of antibodies that bind to a given antigen, no number of species appears to reasonably representative of the breadth of the genus of antibodies that bind the given antigen.
It should be pointed out that 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 antigen. 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 antigen 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.
This applies to the instant invention which is drawn to a subgenus of CARs that comprise a single-chain antibody, an antibody fragment, that binds to CD19, mesothelin, CD20, CD22, CD123, CD30, CD33, CD38, CD138, BCMA, Fibroblast activation protein, Glypican-3, CEA, EGFRvIII, PSMA, Her2, IL13Ra2, CD171, or GD2 which do not comprise a full set of six CDRs.
As noted above, the Applicant has disclosed three CD3ε intracellular regions all of which comprise a basic residue rich sequence (BRS). One of the disclosed CD3ε intracellular regions does not comprise an ITAM or PRS, while the remaining two CD3ε intracellular regions both comprise a PRS and either a wildtype ITAM or a mutant ITAM comprising two Tyr-to-Phe point mutations. Such a disclosure does not serve to provide sufficient written description of the claimed genus of CARs comprising any CD3ε intracellular region with or without any basic residue rich sequence. The disclosure does not identify any specific structural features or combination of features which give rise to a functional CAR comprising a CD3ε intracellular region with or without a basic residue rich sequence. Additionally, there does not appear to be any reasonable shared structure present in the genus of recited CARs which gives rise to their functional activity. Ultimately, identifying a functional CAR simply on the basis of it comprising any CD3ε intracellular region with or without any basic residue rich sequence rather than by identifying the specific sequence/structure, namely for the CD3ε intracellular region, of the CAR in question is generally insufficient to provide written description.
The claims are drawn to a broad genus of CARs comprising any CD3ε intracellular region with or without any basic residue rich sequence which are functional without reciting a corresponding structure expected to correlate with this functionality as supported by Applicant’s disclosure.
Thus, there is insufficient written description for the breadth of CARs comprising any CD3ε intracellular region with or without any basic residue rich sequence as currently claimed, which are distinct and diverse and do not share a common structure that contributes to their functionality.
Regarding subgenus of CARs that comprise a single-chain antibody, an antibody fragment, that binds to CD19, mesothelin, CD20, CD22, CD123, CD30, CD33, CD38, CD138, BCMA, Fibroblast activation protein, Glypican-3, CEA, EGFRvIII, PSMA, Her2, IL13Ra2, CD171, or GD2, as noted above, the Applicant has only disclosed the anti-CD19 single-chain antibody FMC63. Such a disclosure does not serve to provide sufficient written description of the claimed subgenus of CARs that comprise a single-chain antibody, an antibody fragment, that binds to CD19, mesothelin, CD20, CD22, CD123, CD30, CD33, CD38, CD138, BCMA, Fibroblast activation protein, Glypican-3, CEA, EGFRvIII, PSMA, Her2, IL13Ra2, CD171, or GD2.
Further, the disclosure does not identify any specific structural features or combination of features which give rise to the function of binding CD19, mesothelin, CD20, CD22, CD123, CD30, CD33, CD38, CD138, BCMA, Fibroblast activation protein, Glypican-3, CEA, EGFRvIII, PSMA, Her2, IL13Ra2, CD171, or GD2. Additionally, there does not appear to be any reasonable shared structure present in the genus of recited anti-tumor surface antigen CARs which gives rise to their functional activity. Ultimately, identifying an anti-tumor surface antigen CAR simply on the basis of binding CD19, mesothelin, CD20, CD22, CD123, CD30, CD33, CD38, CD138, BCMA, Fibroblast activation protein, Glypican-3, CEA, EGFRvIII, PSMA, Her2, IL13Ra2, CD171, or GD2 rather than by identifying the sequence/structure, namely the CDRs, of the anti-tumor surface antigen CAR in question is generally insufficient to provide written description.
Ultimately, there is insufficient written description for the breadth of CARs that comprise a single-chain antibody, an antibody fragment, that binds to CD19, mesothelin, CD20, CD22, CD123, CD30, CD33, CD38, CD138, BCMA, Fibroblast activation protein, Glypican-3, CEA, EGFRvIII, PSMA, Her2, IL13Ra2, CD171, or GD2.
Therefore, in view of the breadth of the claims and the limited disclosure, artisans would reasonably conclude that applicant was not in possession of the full breadth of CARs encompassed by the claims at the time the instant application was filed.
Amending claim 1 to include that the CAR comprises a CD3ε intracellular region comprising a basic residue rich sequence of SEQ ID NO: 10 and/or two tyrosine-to-phenylalanine mutations in the ITAM and amending claim 5 to recite a full set of six CDRs for the anti-tumor surface antigen single-chain antibody-based antigen recognition region of the extracellular domain of the CAR and its corresponding antigen would obviate this part of the rejection.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-7, 13, and 14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Salter and Riddell 2020 (WO/2020/068702, a reference of record).
Independent claim 1 is drawn to a chimeric antigen receptor comprising an extracellular domain, a transmembrane domain, and an intracellular domain which are connected in sequence; wherein the extracellular domain comprises an antigen recognition region and a hinge region; and one end of the intracellular domain, which is connected to the transmembrane domain, is connected to a CD3ε intracellular region with a Y/F mutation, wherein two tyrosines in the immunoreceptor tyrosine-based activation motif of CD3ε intracellular region with a Y/F mutation are mutated into phenylalanine; or one end of the intracellular domain, which is connected to the transmembrane domain, is connected to a CD3ε intracellular basic residue rich sequence.
Dependent claim 2 limits the CAR of claim 1 to that wherein (1) the amino acid sequence of the CD3ε intracellular region with a Y/F mutation is shown as SEQ ID NO: 1; (2) the intracellular domain comprises the CD3 intracellular region with a Y/F mutation, a costimulatory signaling region, and a CD3𝞯 intracellular segment that are sequentially connected; (3) the amino acid sequence of the CD3ε intracellular basic residue rich sequence is shown as SEQ ID NO: 10; and/or (4) the intracellular domain comprises the CD3ε intracellular basic residue rich sequence, the costimulatory signaling region, and the CD3𝞯 intracellular segment that are sequentially connected.
Dependent claim 3 limits the CAR of claim 2 to that wherein the costimulatory signaling region is selected from one or more of intracellular segments of CD27, CD28, CD 134, 4-1BB, OX40, and ICOS.
Dependent claim 4 limits the CAR of claim 3 to that wherein (1) the amino acid sequence of the CD28 intracellular segment is shown as SEQ ID NO:2; and/or (2) the amino acid sequence of the CD3𝞯 intracellular segment is shown as SEQ ID NO:3.
Dependent claim 5 limits the CAR of claim 1 to that wherein a. the antigen recognition region is selected from a single-chain antibody against a tumor surface antigen, and the tumor surface antigen is selected from one or more of CD 19, mesothelin, CD20, CD22, CD123, CD30, CD33, CD38, CD138, BCMA, Fibroblast activation protein, Glypican-3, CEA, EGFRvIII, PSMA, Her2, IL13Ra2, CD171, and GD2; b. the transmembrane domain is selected from one or more of transmembrane regions of CD28, CD4, CD8a, OX40, and H2-Kb; and/or c. the hinge region is selected from one or more of CD28 hinge region, CD8a hinge region, CD4 hinge region, IgG hinge region, or a coupled hinge region of IgG hinge region and CH2CH3 region.
Dependent claim 6 limits the CAR of claim 5 to that wherein d. the single-chain antibody is selected from FMC63; e. the amino acid sequence of the CD28 transmembrane region is shown as SEQ ID NO:4; and/or f. the amino acid sequence of the CD28 hinge region is shown as SEQ ID NO:7.
Dependent claim 7 limits the CAR of claim 6 to that wherein 1) the antigen recognition region of the chimeric antigen receptor containing the CD3a intracellular region with a Y/F mutation is selected from FMC63, the hinge region is selected from the CD28 hinge region, the transmembrane domain is selected from the CD28 transmembrane region, and the intracellular domain includes the CD3ε intracellular region with a Y/F mutation, the CD28 intracellular segment, and the CD3𝞯 intracellular segment that are sequentially connected; 2) the amino acid sequence of the chimeric antigen receptor containing the CD3ε intracellular region with a Y/F mutation is shown as SEQ ID NO: 5; 3) the antigen recognition region of the chimeric antigen receptor containing the CD3ε intracellular basic residue rich sequence is selected from FMC63, the hinge region is selected from CD28 hinge region, the transmembrane domain is selected from CD28 transmembrane region, and the intracellular domain includes the CD3ε intracellular basic residue rich sequence, the CD28 intracellular segment, and the CD3𝞯 intracellular segment that are sequentially connected; and/or 4) the amino acid sequence of the chimeric antigen receptor containing the CD3ε intracellular basic residue rich sequence is shown as SEQ ID NO: 11.
Dependent claim 13 is drawn to a use of the chimeric antigen receptor according to claim 1 in any one or more of the following: (1) preparing T cells; (2) improving T cell viability; (3) inhibiting T cells from apoptosis; (4) enhancing T cell proliferation and/or viability; (5) improving the anti-tumor effect of T cells; (6) inhibiting T cells from secreting the cytokines IFN-y and TNF-a.
Dependent claim 14 is drawn to a use of the chimeric antigen receptor according to claim 1 in the preparation of tumor treatment products.
Regarding claim 1, Salter and Riddell teach a chimeric antigen receptors (CAR) that comprises an extracellular domain comprising an antigen recognition region, a transmembrane domain, and an intracellular domain which are connected in sequence (e.g. see page 6, lines 13-17). Salter and Riddell also teach that the extracellular domain comprises a hinge region (e.g. see page 39, lines 21-30). Salter and Riddell also teach that one end of the intracellular domain which is connected to the transmembrane domain and comprises an effector domain or a functional portion or variant thereof, wherein the effector domain or functional portion thereof may comprise an (i) Intracellular Tyrosine-based Activation Motif (ITAM) from CD3ε, or a functional portion or variant thereof, (ii) a Basic Residue Rich Sequence (BRS) from CD3ε, or a functional portion or variant thereof; or (iii) any combination of (i)-(iii) (e.g. see page 6, lines 18-24). Salter and Riddell also teach an exemplary BRS from CD3ε is provided in SEQ ID NO: 9 (KNRKAKAK) and an exemplary sequence of a human CD3ε cytoplasmic domain containing a BRS, a PRS, and an ITAM is provided in SEQ ID SEQ ID NO: 111 with the BRS bolded and underlined (KNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI).
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Regarding claim 2, it is noted that SEQ ID NO: 1 is identical to instant SEQ ID NO: 10. See sequence alignment below.
Further regarding claim 2 and regarding claim 3, Salter and Riddell teach that the intracellular domain comprises a costimulatory domain and a CD3ζ intracellular segment that are sequentially connected, wherein the costimulatory domain is CD27, CD28, CD134, 4-1BB, OX40, and ICOS (e.g. see page 35, line 30 – page 36, line 4).
Regarding claims 5-7, Salter and Riddell also teach that the tumor surface antigen is CD19, CD20, CD22, EGFRvIII, GD2, Her2, PSMA, CD30, CD33, CD38, IL-13Rα2, mesothelin, BCMA, FAP, or CEA antigen (e.g. see page 33, lines 3-13); that the transmembrane domain is a CD4 transmembrane domain, a CD8 transmembrane domain, a CD28 transmembrane domain, or any combination thereof (e.g. see page 37, line 27-page 38, line 10); and an IgG hinge (e.g. see page 78, lines 7-13) or that the extracellular domain comprises a CH1, a CH2, a CH3, a CL (i.e., from an immunoglobulin), or comprises an amino acid sequence derived therefrom, a CD8 extracellular domain, a CD4 extracellular domain, a CD28 extracellular domain (e.g., amino acids 19-152 of the CD28 amino acid sequence provided in UniProt entry P10747) or a functional variant or portion thereof, or comprises a combination thereof (e.g. see page 78, lines 7-13).
Regarding claims 6 and 7, Salter and Riddell also teach that extracellular domain comprises a CD19-specific scFv derived from FMC63 (e.g. see page 33, lines 13-20).
Regarding claims 13 and 14, teach the preparation of CAR T cells for treating tumor cells (e.g. see page 104, lines 15-26).
Regarding the amino acid sequences recited in claims 4 and 6 for the intracellular segments, transmembrane domain, and hinge region, it is noted that the claimed amino acid sequences are the wildtype sequences of the respective domains. Therefore, given that Salter and Riddell teach the individual components, the domains would inherently have the wildtype amino acid sequences as recited in the claims, especially without evidence to the contrary.
As such, claims 1-7, 13, and 14 are anticipated by Salter and Riddell.
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.
Claims 1-4, 13, and 14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2-4 of co-pending U.S. Application No. 18/009,713 (the ‘713 Application).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims and the claims in the reference application are drawn to the same or nearly the same chimeric antigen receptor having the same or nearly the same structure.
The instant claims are drawn to a chimeric antigen receptor comprising an extracellular domain, a transmembrane domain, and an intracellular domain which are connected in sequence; wherein the extracellular domain comprises an antigen recognition region and a hinge region; and one end of the intracellular domain, which is connected to the transmembrane domain, is connected to a CD3ε intracellular region with a Y/F mutation, wherein two tyrosines in the immunoreceptor tyrosine-based activation motif of CD3ε intracellular region with a Y/F mutation are mutated into phenylalanine; or one end of the intracellular domain, which is connected to the transmembrane domain, is connected to a CD3ε intracellular basic residue rich sequence.
The claims in the ‘713 Application are drawn to a chimeric antigen receptor, comprises: an extracellular domain, a transmembrane domain, and an intracellular domain which are connected in sequence, wherein the extracellular domain comprises an antigen recognition region and a hinge region; and one end of the intracellular domain which is connected to the transmembrane domain is connected to a CD3ε intracellular region; wherein the intracellular domain comprises the CD3ε intracellular region, a costimulatory signaling region, and a CD3K intracellular region that are sequentially connected, wherein he amino acid sequence of the CD3ε intracellular region is shown as SEQ ID NO: 1
Therefore, the claims of the reference application recite a “species” of the generic invention of the instant claims. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993).
Thus, the reference’s teachings anticipate the instant invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 2, 13, and 14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2 and 3 of co-pending U.S. Application No. 19/497,547 (the ‘547 Application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims and the claims in the reference application are drawn to the same or nearly the same chimeric antigen receptor having the same or nearly the same structure.
The instant claims are drawn to a chimeric antigen receptor comprising an extracellular domain, a transmembrane domain, and an intracellular domain which are connected in sequence; wherein the extracellular domain comprises an antigen recognition region and a hinge region; and one end of the intracellular domain, which is connected to the transmembrane domain, is connected to a CD3ε intracellular region with a Y/F mutation, wherein two tyrosines in the immunoreceptor tyrosine-based activation motif of CD3ε intracellular region with a Y/F mutation are mutated into phenylalanine; or one end of the intracellular domain, which is connected to the transmembrane domain, is connected to a CD3ε intracellular basic residue rich sequence.
The claims in the ‘547 Application are drawn to a chimeric antigen receptor, comprising: an extracellular domain, a transmembrane domain, and an intracellular domain, which are sequentially connected; wherein the extracellular domain comprises an antigen-binding region and a hinge region; and wherein the intracellular domain comprises, in sequence, a truncated CD3ε intracellular region, a costimulatory signaling region, and a CD3ζ intracellular region, wherein, compared to a CD3ε intracellular region, the truncated CD3ε intracellular region consists of a BRS sequence, a linker sequence, and an ITAM sequence linked in sequence.
Therefore, the claims of the reference application recite a “species” of the generic invention of the instant claims. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993).
Thus, the reference’s teachings anticipate the instant invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-7, 13, and 14 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-20 of U.S. Application No. 18/009,713 (the ‘713 Application) in view of Bettini et al. 2014 (J Immunol. 193(1): 258–267).
The instant claims are drawn to a chimeric antigen receptor comprising an extracellular domain, a transmembrane domain, and an intracellular domain which are connected in sequence; wherein the extracellular domain comprises an antigen recognition region and a hinge region; and one end of the intracellular domain, which is connected to the transmembrane domain, is connected to a CD3ε intracellular region with a Y/F mutation, wherein two tyrosines in the immunoreceptor tyrosine-based activation motif of CD3ε intracellular region with a Y/F mutation are mutated into phenylalanine; or one end of the intracellular domain, which is connected to the transmembrane domain, is connected to a CD3ε intracellular basic residue rich sequence.
The claims in the ‘713 Application are drawn to a chimeric antigen receptor, comprises: an extracellular domain, a transmembrane domain, and an intracellular domain which are connected in sequence, wherein the extracellular domain comprises an antigen recognition region and a hinge region; and one end of the intracellular domain which is connected to the transmembrane domain is connected to a CD3ε intracellular region; wherein the intracellular domain comprises the CD3ε intracellular region, a costimulatory signaling region, and a CD3K intracellular region that are sequentially connected.
The claims in the ‘713 Application differ from the instant invention by not reciting that the CD3ε intracellular region comprises a BRS.
The teachings of Bettini et al. are discussed in the Written Description rejection above.
It would be prima facie obvious to one of ordinary skill in the art to modify the claims in the ‘713 Application and to incorporate the teachings of Bettini et al. to include that the CD3ε intracellular region comprises a BRS. This is because the BRS of CD3ε plays a critical physiological role in regulating TCR signaling, thereby facilitating optimal T cell development, peripheral T cell function and the generation of protective immunity (Bettini et al.).
Given that mutating only three of the six residues in the BRS significantly impacts not only thymocyte differentiation but also subsequent TCR expression and signaling capacity and thymocytes expressing CD3ε-BRS mutations exhibited cell intrinsic defects and were at a competitive disadvantage compared with WT thymocytes; it would be obvious to a skilled artisan, the goal of designing a function CAR, to include that the CD3ε intracellular region comprises a wildtype full length BRS with a reasonable expectation of success.
In order to have a functional CD3ε intracellular signaling region that allows for proper regulation of TCR signaling, thereby facilitating optimal T cell development, peripheral T cell function and the generation of protective immunity, the CD3ε intracellular signaling region must comprise at least a wildtype full-length BRS. Therefore, a skilled artisan would reasonably expect that the inclusion of a wildtype full-length BRS in the CAR of the ‘713 Application would be required for proper CAR function.
Therefore, the claims in the ‘713 Application would render the instant claims obvious.
This is a provisional nonstatutory double patenting rejection because the reference claims have not in fact been patented.
Claims 1-7, 13, and 14 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-19 of U.S. Application No. 19/497,547 (the ‘547 Application) in view of Bettini et al. 2014 (J Immunol. 193(1): 258–267).
The instant claims are drawn to a chimeric antigen receptor comprising an extracellular domain, a transmembrane domain, and an intracellular domain which are connected in sequence; wherein the extracellular domain comprises an antigen recognition region and a hinge region; and one end of the intracellular domain, which is connected to the transmembrane domain, is connected to a CD3ε intracellular region with a Y/F mutation, wherein two tyrosines in the immunoreceptor tyrosine-based activation motif of CD3ε intracellular region with a Y/F mutation are mutated into phenylalanine; or one end of the intracellular domain, which is connected to the transmembrane domain, is connected to a CD3ε intracellular basic residue rich sequence.
The claims in the ‘547 Application are drawn to a chimeric antigen receptor, comprising: an extracellular domain, a transmembrane domain, and an intracellular domain, which are sequentially connected; wherein the extracellular domain comprises an antigen-binding region and a hinge region; and wherein the intracellular domain comprises, in sequence, a truncated CD3ε intracellular region, a costimulatory signaling region, and a CD3ζ intracellular region; a polynucleotide sequence; a nucleic acid construct; a lentiviral vector system; a genetically modified T cell; a method for preparing a product comprising the chimeric antigen receptor; method for preparing a product for tumor therapy; and a method for treating a tumor.
The claims in the ‘547 Application differ from the instant invention by not reciting that the CD3ε intracellular region comprises a BRS.
The teachings of Bettini et al. are discussed in the Written Description rejection above.
It would be prima facie obvious to one of ordinary skill in the art to modify the claims in the ‘547 Application and to incorporate the teachings of Bettini et al. to include that the CD3ε intracellular region comprises a BRS. This is because the BRS of CD3ε plays a critical physiological role in regulating TCR signaling, thereby facilitating optimal T cell development, peripheral T cell function and the generation of protective immunity (Bettini et al.).
Given that mutating only three of the six residues in the BRS significantly impacts not only thymocyte differentiation but also subsequent TCR expression and signaling capacity and thymocytes expressing CD3ε-BRS mutations exhibited cell intrinsic defects and were at a competitive disadvantage compared with WT thymocytes; it would be obvious to a skilled artisan, the goal of designing a function CAR, to include that the CD3ε intracellular region comprises a wildtype full length BRS with a reasonable expectation of success.
In order to have a functional CD3ε intracellular signaling region that allows for proper regulation of TCR signaling, thereby facilitating optimal T cell development, peripheral T cell function and the generation of protective immunity, the CD3ε intracellular signaling region must comprise at least a wildtype full-length BRS. Therefore, a skilled artisan would reasonably expect that the inclusion of a wildtype full-length BRS in the CAR of the ‘547 Application would be required for proper CAR function.
Regarding the reference claims that are drawn to nucleic acids, it is noted that obtaining cDNA/nucleic acids from protein sequences has been routine and conventional in the art and used to make proteins of interest, including CARs of interest. For example, expression vectors can comprise polynucleotides sequences encoding amino acids, in turn CARs. Given that obtaining cDNA/nucleic acids from protein sequence sequences is routine and conventional, it would have been obvious to the ordinary artisan to obtaining cDNA to produce proteins of interest.
This applies to the instant case where it would be obvious to a skilled artisan to obtain the instant CAR from the polynucleotides of the ‘547 Application.
Therefore, the claims in the ‘547 Application would render the instant claims obvious.
This is a provisional nonstatutory double patenting rejection because the reference claims have not in fact been patented.
Conclusion
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/GRACE H LUNDE/Examiner, Art Unit 1641 /MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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