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 1-4, 6, 8, 13, 17-18, 22, 25, 28-30 and 32-37 are pending.
Applicant’s election without traverse of a method for assessing responsiveness of a subject to a treatment comprising T cells expressing a particular bivalent BCMA-targeting chimeric antigen receptor (CAR) that read on (A) CD8a as the transmembrane domain, (B) CD3zeta as the primary intracellular signaling domain and (C) CD137 as the particular co-stimulatory signaling domain and (D) multiple myeloma as the species of cancer in the reply filed on July 7, 2026 is acknowledged.
Claims 1-4, 6, 8, 13, 17-18, 22, 25, 28-30 and 32-37, drawn to a method for assessing responsiveness of a subject to a treatment comprising T cells expressing a particular bivalent BCMA-targeting chimeric antigen receptor (CAR) that read on (A) CD8a as the transmembrane domain, (B) CD3zeta as the primary intracellular signaling domain and (C) CD137 as the particular co-stimulatory signaling domain and (D) multiple myeloma as the species of cancer, are being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 63/421,740, filed November 2, 2022, is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on July 7, 2026, August 16, 2024 and February 2, 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 November 1, 2023 are acceptable.
Specification
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 Objections
Claims 33-34 are objected to because of the following informality: “post the treatment” should have been “post treatment”.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 22 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claim 22 recites the trademark/trade name “clonoSEQ”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112, second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name “ClonoSEQ®” is used to identify/describe testing service and, accordingly, the identification/description is indefinite.
Claim rejections under - 35 U.S.C. 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 1-4, 6, 8, 13, 17-18, 22, 25, 28-30 and 32-37 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 1 encompasses a method for assessing responsiveness of a subject to a treatment comprising T cells expressing a bivalent BCMA-targeting chimeric antigen receptor (CAR), comprising: (a) administering to the subject the T cells; (b) measuring time length the subject maintains minimal residual disease (MRD) negative status; and (c) assessing the responsiveness of the subject to the treatment based on that (i) the MRD negative status is maintained for shorter than 6 months;(ii) the MRD negative status is maintained for at least 6 months and shorter than 12 months; or (iii) the MRD negative status is maintained for at least 12 months, wherein the bivalent BCMA-targeting CAR comprises an extracellular antigen binding domain comprising a first VHH domain and a second VHH domain, a transmembrane domain, and an intracellular signaling domain, wherein the first VHH domain comprises a CDR1, a CDR2, and a CDR3 as set forth in the VHH domain comprising the amino acid sequence of SEQ ID NO: 2, and the second VHH domain comprises a CDR1, a CDR2, and a CDR3 as set forth in the VHH domain comprising the amino acid sequence of SEQ ID NO: 4.
Claim 2 encompasses the method of claim 1, wherein the first VHH domain comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 18, a CDR2 comprising the amino acid sequence of SEQ ID NO: 19, a CDR3 comprising the amino acid sequence of SEQ ID NO: 20; and the second VHH domain comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 21, a CDR2 comprising the amino acid sequence of SEQ ID NO: 22, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 23.
Claim 3 encompasses the method of claim 1, wherein the first VHH domain comprises the amino acid sequence of SEQ ID NO: 2 and the second VHH domain comprises the amino acid sequence of SEQ ID NO: 4.
Claim 4 encompasses the method of claim 1, wherein the first VHH domain is at the N- terminus of the second VHH domain, or the first VHH domain is at the C-terminus of the second VHH domain, wherein optionally the first VHH domain is linked to the second VHH domain via a linker comprising the amino acid sequence of SEQ ID NO: 3.
Claim 6 encompasses the method of claim 1, wherein the transmembrane domain is derived from a molecule selected from the group consisting of CD8a (elected species), CD4, CD28, CD137, CD80, CD86, CD152 and PD 1, wherein optionally the transmembrane domain is derived from CD8a and comprises the amino acid sequence of SEQ ID NO: 6.
Claim 8 encompasses the method of claim 1, wherein: (1) the intracellular signaling domain comprises a primary intracellular signaling domain of an immune effector cell, wherein optionally the primary intracellular signaling domain is derived from CD3ζ comprising the amino acid sequence of SEQ ID NO: 8; or (2) the intracellular signaling domain comprises a co-stimulatory signaling domain, wherein optionally the co-stimulatory signaling domain is derived from a co-stimulatory molecule selected from the group consisting of CD27, CD28, CD 137, OX40, CD30, CD40, CD3, LFA-1, ICOS, CD2, CD7, LIGHT, NKG2C, B7-H3, ligands of CD83 and any combination thereof, wherein further optionally the co-stimulatory signaling domain comprises a cytoplasmic domain of CD137 (elected species) comprising the amino acid sequence of SEQ ID NO: 7.
Claim 13 encompasses the method of claim 1, wherein the CAR further comprises: (1) a hinge domain located between the C-terminus of the extracellular antigen binding domain and the N-terminus of the transmembrane domain, wherein optionally the hinge domain is derived from CD8α comprising the amino acid sequence of SEQ ID NO: 5; or (2) a signal peptide located at the N-terminus of the polypeptide, wherein optionally the signal peptide is derived from CD8a comprising the amino acid sequence of SEQ ID NO: 1.
Claim 17 encompasses the method of claim 1, wherein the CAR comprises the amino acid sequence of SEQ ID NO: 17.
Claim 18 encompasses the method of claim 1, wherein the subject has a disease or disorder, wherein optionally the disease or disorder is cancer, wherein further optionally the cancer is multiple myeloma, and wherein further optionally the cancer is refractory or relapsed multiple myeloma.
Claim 22 encompasses the method of claim 1, wherein the method comprises obtaining bone marrow aspirate or biopsy from the subject for assessing MRD status, wherein optionally the MRD status is monitored using next generation sequencing (NGS) of bone marrow aspirate DNA, wherein further optionally the NGS is performed via clonoSEQ.
Claim 25 encompasses the method of claim 22, wherein baseline bone marrow aspirates are used to define the myeloma clones, and post-treatment samples are used to evaluate MRD negativity, wherein optionally evaluable samples are those that passed one or more of, or all of, calibration, quality control, and sufficiency of cells evaluable at a particular sensitivity level, wherein further optionally the sensitivity level is about 10-6, 10-5,10-4, or 10-3.
Claim 28 encompasses the method of claim 1, wherein the time length the subject maintains MRD negative status is measured from the time when MRD is first achieved in the subject.
Claim 29 encompasses the method of claim 1, wherein the method comprises assessing the likelihood of the subject to have complete response (CR), partial response (PR), stringent CR (sCR), or very good PR (VGPR).
Claim 30 encompasses the method of claim 29, comprising determining that the subject is likely to have CR, PR, sCR, or VGPR if the MRD negative status is maintained for shorter than 6 months in the subject, or determining that the subject is likely to have CR or sCR if the MRD negative status is maintained for longer than 6 months in the subject.
Claim 32 encompasses the method of claim 1, wherein the method comprises assessing the likelihood of the subject to have progression-free survival.
Claim 33 encompasses the method of claim 32, comprising determining that the subject is likely to have progression-free survival for at least 12 months post the treatment if the MRD negative status is maintained for longer than 6 months in the subject.
Claim 34 encompasses the method of claim 32, comprising determining that the subject is likely to have progression-free survival for at least 24 months post the treatment if the MRD negative status is maintained for longer than 12 months in the subject.
Claim 35 encompasses the method of claim 1, wherein the method comprises assessing duration of response in the subject.
Claim 36 encompasses the method of claim 35, comprising determining that the subject is likely to have a duration of response of more than 12 months if the MRD negative status is maintained for longer than 6 months in the subject.
Claim 37 encompasses the method of claim 36, comprising determining that the subject is likely to have a duration of response of more than 24 months if the MRD negative status is maintained for longer than 12 months in the subject.
The specification discloses a method for assessing responsiveness of a subject treated with ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T (CAR-T) cell therapy with two B-cell maturation antigen (BCMA)-targeting single-domain antibodies comprising the amino acid sequence of SEQ ID NO: 2 linked to SEQ ID NO: 4 via a linker of SEQ ID NO: 3, a CD8α transmembrane domain comprising the amino acid sequence of SEQ ID NO: 6, a co-stimulatory signaling domain from CD137 comprising the amino acid sequence of SEQ ID NO: 7, and a CD3ζ intracellular domain comprising the amino acid sequence of SEQ ID NO: 8. The bivalent BCMA-targeting chimeric antigen receptor (CAR) comprises the amino acid sequence of SEQ ID NO: 17. Minimal residual disease (MRD) negativity at 10-5 was assessed by next-generation sequencing (NGS) on bone marrow aspirate or biopsy. DNA Baseline bone marrow aspirates were used to define the myeloma clones, and post-treatment samples were used to evaluate MRD negativity. A fresh bone marrow aspirate was collected prior to the first dose of conditioning regimen (≤7 days). MRD was assessed at baseline, day 28, and 6-, 12-, 18-, and 24-month follow-ups using next-generation sequencing (clonoSEQ version 2.0) (Adaptive Biotechnologies, Seattle, WA, USA) in patients at the time of suspected complete response, and then every 12 months until disease progression for patients who remained on study. MRD negativity was assessed in samples that passed calibration or quality control and included sufficient cells for evaluation at the testing threshold of 10.sup.−5. Durability of MRD-negative status was evaluated by estimating MRD negativity rates at 6- and 12-month follow-ups.
However, the specification does not describe the structure of any and all potential bivalent BCMA-targeting chimeric antigen receptor (CAR) comprises an extracellular antigen binding domain comprising just a first VHH domain and a second VHH domain, a transmembrane domain, and an intracellular signaling domain, wherein the first VHH domain comprises a CDR1, a CDR2, and a CDR3 as set forth in the VHH domain comprising the amino acid sequence of SEQ ID NO: 2, and the second VHH domain comprises a CDR1, a CDR2, and a CDR3 as set forth in the VHH domain comprising the amino acid sequence of SEQ ID NO: 4 without transmembrane spacer, intracellular signaling domain and costimulatory signaling domain (claims 1-4).
Regarding transmembrane domain “derived” from any molecule such as CD8α (claim 6), the specification discloses just one CD8α transmembrane domain comprises the amino acid sequence of SEQ ID NO: 6.
However, the term “derived” encompasses any substitution, deletion, addition or a combination thereof. The specification does not describe where and what amino acids within the transmembrane domain of any CD8α to be substituted, deleted, added or a combination thereof such that the derivative still maintains the distance for the extracellular domain to bind to BCMA. The specification does not describe the structure, e.g., amino acid sequence of such derivative. The specification does not describe the structure of a sufficient number of species of the genus to reasonably convey to the skilled artisan that Applicant had possession of the claimed invention at the time the application was filed.
Furthermore, the term “optionally” in claim 6 may or may not comprises the amino acid sequence of SEQ ID NO: 6.
Regarding optionally the primary intracellular signaling is derived from CD3ζ comprising the amino acid sequence of SEQ ID NO: 8 (claim 8), the term “optionally” may or may not include the primary intracellular signaling from CD3ζ. The term “derived” encompasses any substitution, deletion, addition or a combination thereof. The specification does not describe where and what amino acids within the primary intracellular domain of CD3ζ to be substituted, deleted, added or a combination thereof such that derivative of CD3ζ still maintains its 3-D structure and signaling function. The specification does not describe a representative number of species for the claimed genus.
Regarding optionally the co-stimulatory signal domain is derived from CD137 or any combination thereof, wherein further optionally the co-stimulatory signaling domain comprising the amino acid sequence of SEQ ID NO: 7 (claim 8), the first “optionally” may or may not include the co-stimulatory signal domain. The second “optionally” may or may not include the co-stimulatory signaling domain comprising the amino acid sequence of SEQ ID NO: 7. Furthermore, the term “derived” encompasses any substitution, deletion, addition or a combination thereof. The specification does not describe where and what amino acids within the costimulatory signaling domain from any CD27, CD28, CD 137, OX40, CD30, CD40, CD3, LFA-1, ICOS, CD2, CD7, LIGHT, NKG2C, B7-H3, ligands of CD83 and any combination thereof to be substituted, deleted, added or a combination thereof such that the modified derivative still maintains co-stimulatory signaling encompassed by the bivalent BCMA-targeting chimeric antigen receptor. The specification does not describe the structure, e.g., amino acid sequence of any derivative of co-stimulatory signal domain from CD137, CD27, CD28, CD 137, OX40, CD30, CD40, CD3, LFA-1, ICOS, CD2, CD7, LIGHT, NKG2C, B7-H3, ligands of CD83 and a combination thereof. The specification does not describe a representative number of species for the claimed genus.
Regarding optionally the hinge domain is derived from CD8α comprising the amino acid sequence of SEQ ID NO: 5 and optionally the signal peptide derived from CD8α comprising the amino acid sequence of SEQ ID NO: 1 (claim 13), the specification discloses just a hinge domain from CD8α comprising the amino acid sequence of SEQ ID NO: 5 and a signal peptide from CD8α comprising the amino acid sequence of SEQ ID NO: 1.
However, the specification does not describe the structure, e.g., amino acid sequence of any derivative of CD8α hinge domain or any derivative of CD8α signal peptide. The specification does not describe a representative number of species for the claimed genus.
For example, Bernard (Frontiers in Immunology 16: 1664403, Oct 27, 2025; PTO 892) teaches that the chimeric antigen receptor (CAR) is a synthetic and modular molecule composed of both signaling and non-signaling domains that allows a T cell to recognize cell surface antigens and trigger cytolytic functionality. It is appreciated that the non-signaling structural components, including the linker, hinge, and transmembrane domains, can dramatically alter how the CAR molecule interacts with itself and other endogenous molecules in the immune synapse, see entire document, abstract, in particular. Bernard teaches that the properties of the hinge, including its identity and length, shape how the CAR responds to antigen density and epitope position, ultimately affecting sensitivity and signaling strength, see p. 3, right col. The length of the hinge contributes to the overall functionality of a CAR in an antigen-and epitope-specific manner, see p. 4, left col. There is not a one size-fits-all approach to hinge engineering and that optimization is required for each CAR. Nonetheless, understanding the properties of the scFv (i.e. affinity, oligomerization propensity), the position of the target epitope on the antigen and its proximity to the membrane, as well as overall antigen density may help to predict a ‘goldilocks’ hinge identity and length. Thus, a representative number of species falling within the scope of the genus of bivalent-targeting chimeric antigen receptor encompassed by the claims or structural features common to members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus are not adequately described.
Regarding “optionally” the MRD status is monitored using next generation sequencing (NGS)…further optionally the NGS is performed via clonoSEQ (claim 22), the specification discloses the use of just next generation sequencing (NGS) or clonoSEQ to assess minimal residual disease (MRD) negative status of the patient treated with Ciltacabtagene Autoleucel.
However, the term “optionally” may or may not use next generation sequencing (NGS) or clonoSEQ to assess minimal residual disease (MRD) negative status. It is not clear what is being used for assessing MRD encompassed by the claimed method.
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. Thus, the specification fails to describe these DNA sequences.
For genus claims, an adequate written description of a claimed genus requires more than a generic statement of an invention's boundaries. A patent must set forth either a representative number of species falling within the scope of the genus or structural features common to the members of the genus. Kubin, Exparte, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007); Ariad Pharms., Inc. v. Eli Lilly& Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010).
Therefore, only a method for assessing responsiveness of a subject to a treatment comprising T cells expressing a bivalent BCMA-targeting chimeric antigen receptor (CAR), the method comprises (a) administering to the subject the T cells, (b) providing a cell sample from the subject, (c) measuring time length the subject maintains minimal residual disease (MRD) negative status using next generation sequencing (NGS), and (d), assessing the responsiveness of the subject to the treatment based on that (i) the MRD negative status is maintained for shorter than 6 months; (ii) the MRD negative status is maintained for at least 6 months and shorter than 12 months; or (iii) the MRD negative status is maintained for at least 12 months, wherein the bivalent BCMA-targeting CAR comprises an extracellular antigen binding domain comprising a first VHH domain and a second VHH domain, a transmembrane domain, and an intracellular signaling domain, wherein the first VHH domain comprises a CDR1, a CDR2, and a CDR3 as set forth in the VHH domain comprising the amino acid sequence of SEQ ID NO: 2, and the second VHH domain comprises a CDR1, a CDR2, and a CDR3 as set forth in the VHH domain comprising the amino acid sequence of SEQ ID NO: 4, a linker of SEQ ID NO: 3, a CD8α transmembrane domain comprising the amino acid sequence of SEQ ID NO: 6, a co-stimulatory signaling domain from CD137 comprising the amino acid sequence of SEQ ID NO: 7, and a CD3ζ intracellular domain comprising the amino acid sequence of SEQ ID NO: 8, (2) the said method wherein the bivalent BCMA-targeting chimeric antigen receptor (CAR) comprises the amino acid sequence of SEQ ID NO: 17, (3) the said method wherein the cell sample comprises a bone marrow aspirate or a biopsy sample, (4) the said method wherein the cell sample is a baseline bone marrow aspirate sample for defining myeloma clones, or wherein the samples is a post-treatment sample that passed one or more calibration, quality control, and sufficiency of cells at a sensitivity level from about 10-6, 10-5, 10-4, or 10-3, (5) the said method further comprises assessing likelihood of the subject to have complete response (CR), partial response (PR), stringent CR (sCR), or very good PR (VGPR), (6) the said method wherein the subject is likely to have CR, PR, sCR, or VGPR if the MRD negative status is maintained for shorter than 6 months in the subject, or determining that the subject is likely to have CR or sCR if the MRD negative status is maintained for longer than 6 months in the subject, (7) the said method wherein the subject is likely to have progression-free survival for at least 12 months post the treatment if the MRD negative status is maintained for longer than 6 months in the subject, (8) the said method wherein the subject is likely to have progression-free survival for at least 24 months post the treatment if the MRD negative status is maintained for longer than 12 months in the subject, (9) the said method wherein the subject is likely to have a duration of response of more than 12 months if the MRD negative status is maintained for longer than 6 months in the subject, (10) the said method wherein the subject is likely to have a duration of response of more than 24 months if the MRD negative status is maintained for longer than 12 months in the subject, 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).
Claim Rejections - 35 USC § 102
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 1-4, 6, 8, 13, 17-18, 22, 23, 28, 29, 32 and 35 are rejected under 35 U.S.C. 102 (a)(1)as being anticipated by Stirner (WO2021207689 publication, published Oct 14, 2021; PTO 892).
Claim 1 recites a method for assessing responsiveness of a subject to a treatment comprising T cells expressing a bivalent BCMA-targeting chimeric antigen receptor (CAR), comprising: (a) administering to the subject the T cells; (b) measuring time length the subject maintains minimal residual disease (MRD) negative status; and (c) assessing the responsiveness of the subject to the treatment based on that (i) the MRD negative status is maintained for shorter than 6 months;(ii) the MRD negative status is maintained for at least 6 months and shorter than 12 months; or (iii) the MRD negative status is maintained for at least 12 months, wherein the bivalent BCMA-targeting CAR comprises an extracellular antigen binding domain comprising a first VHH domain and a second VHH domain, a transmembrane domain, and an intracellular signaling domain, wherein the first VHH domain comprises a CDR1, a CDR2, and a CDR3 as set forth in the VHH domain comprising the amino acid sequence of SEQ ID NO: 2, and the second VHH domain comprises a CDR1, a CDR2, and a CDR3 as set forth in the VHH domain comprising the amino acid sequence of SEQ ID NO: 4.
Claim 2 recites the method of claim 1, wherein the first VHH domain comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 18, a CDR2 comprising the amino acid sequence of SEQ ID NO: 19, a CDR3 comprising the amino acid sequence of SEQ ID NO: 20; and the second VHH domain comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 21, a CDR2 comprising the amino acid sequence of SEQ ID NO: 22, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 23.
Claim 3 recites the method of claim 1, wherein the first VHH domain comprises the amino acid sequence of SEQ ID NO: 2 and the second VHH domain comprises the amino acid sequence of SEQ ID NO: 4.
Claim 4 recites the method of claim 1, wherein the first VHH domain is at the N- terminus of the second VHH domain, or the first VHH domain is at the C-terminus of the second VHH domain, wherein optionally the first VHH domain is linked to the second VHH domain via a linker comprising the amino acid sequence of SEQ ID NO: 3.
Claim 6 recites the method of claim 1, wherein the transmembrane domain is derived from a molecule selected from the group consisting of CD8a (elected species), CD4, CD28, CD137, CD80, CD86, CD152 and PD 1, wherein optionally the transmembrane domain is derived from CD8a and comprises the amino acid sequence of SEQ ID NO: 6.
Claim 8 recites the method of claim 1, wherein: (1) the intracellular signaling domain comprises a primary intracellular signaling domain of an immune effector cell, wherein optionally the primary intracellular signaling domain is derived from CD3ζ comprising the amino acid sequence of SEQ ID NO: 8; or (2) the intracellular signaling domain comprises a co-stimulatory signaling domain, wherein optionally the co-stimulatory signaling domain is derived from a co-stimulatory molecule selected from the group consisting of CD27, CD28, CD 137, OX40, CD30, CD40, CD3, LFA-1, ICOS, CD2, CD7, LIGHT, NKG2C, B7-H3, ligands of CD83 and any combination thereof, wherein further optionally the co-stimulatory signaling domain comprises a cytoplasmic domain of CD137 (elected species) comprising the amino acid sequence of SEQ ID NO: 7.
Claim 13 recites the method of claim 1, wherein the CAR further comprises: (1) a hinge domain located between the C-terminus of the extracellular antigen binding domain and the N-terminus of the transmembrane domain, wherein optionally the hinge domain is derived from CD8α comprising the amino acid sequence of SEQ ID NO: 5; or (2) a signal peptide located at the N-terminus of the polypeptide, wherein optionally the signal peptide is derived from CD8a comprising the amino acid sequence of SEQ ID NO: 1.
Claim 17 recites the method of claim 1, wherein the CAR comprises the amino acid sequence of SEQ ID NO: 17.
Claim 18 recites the method of claim 1, wherein the subject has a disease or disorder, wherein optionally the disease or disorder is cancer, wherein further optionally the cancer is multiple myeloma, and wherein further optionally the cancer is refractory or relapsed multiple myeloma.
Claim 22 recites the method of claim 1, wherein the method comprises obtaining bone marrow aspirate or biopsy from the subject for assessing MRD status, wherein optionally the MRD status is monitored using next generation sequencing (NGS) of bone marrow aspirate DNA, wherein further optionally the NGS is performed via clonoSEQ.
Claim 25 recites the method of claim 22, wherein baseline bone marrow aspirates are used to define the myeloma clones, and post-treatment samples are used to evaluate MRD negativity, wherein optionally evaluable samples are those that passed one or more of, or all of, calibration, quality control, and sufficiency of cells evaluable at a particular sensitivity level, wherein further optionally the sensitivity level is about 10-6, 10-5,10-4, or 10-3.
Claim 28 recites the method of claim 1, wherein the time length the subject maintains MRD negative status is measured from the time when MRD is first achieved in the subject.
Claim 29 recites the method of claim 1, wherein the method comprises assessing the likelihood of the subject to have complete response (CR), partial response (PR), stringent CR (sCR), or very good PR (VGPR).
Regarding claim 1, 2, 3, 4, 6, 8, 13, 17, Stirner teaches a method for assessing responsiveness (p. 57, para. [0179]) of a subject, e.g., human to a treatment comprising T cells expressing multivalent (see para. [0058]) BCMA-targeting chimeric antigen receptor (CAR), p, 48, para. [0160], see p. 49, para. [0162], assessing the response using minimal residua disease (MRD) in the marrow using Next generation sequence, also known as NGS, see p. 57, para. [0180]). The sustained MRD-negative includes subject that exhibit MRD negativity at a minimum of 1 year (aka at least 12 months) to duration of negativity, e.g., MRD-negative at 5 years, see p. 57, para. [0180].
Regarding claim 17, Stirner teaches that the multivalent CAR comprises the amin acid sequence of SEQ ID NO: 267, see para. [0058]. The reference SEQ ID NO: 267 comprises the claimed bivalent BCMA-targeting CAR comprising the amino acid sequence identical to the claimed SEQ ID NO: 17, see sequence alignment below, signal peptide in bold and underline at the N-terminus, follow by first VHH, which is identical to the claimed SEQ ID NO: 2 as per claim 2, wherein the 3CDRs are in bold, follows by a GGGGS linker, which is underline and identical to instant SEQ ID NO: 3 as per claim 3, wherein the linker is linked to the italic sequence, which is the second VHH of instant SEQ ID NO: 4, wherein the second VHH comprises the 3 CDRs in italic and bold, the transmembrane domain in red is identical to the claimed SEQ ID NO: 6, see reference p. 284, in particular:
ALIGNMENT:
Query Match 100.0%; Score 2553; Length 488;
Best Local Similarity 100.0%;
Matches 488; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MALPVTALLLPLALLLHAARPQVKLEESGGGLVQAGRSLRLSCAASEHTFSSHVMGWFRQ 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MALPVTALLLPLALLLHAARPQVKLEESGGGLVQAGRSLRLSCAASEHTFSSHVMGWFRQ 60
Qy 61 APGKERESVAVIGWRDISTSYADSVKGRFTISRDNAKKTLYLQMNSLKPEDTAVYYCAAR 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 APGKERESVAVIGWRDISTSYADSVKGRFTISRDNAKKTLYLQMNSLKPEDTAVYYCAAR 120
Qy 121 RIDAADFDSWGQGTQVTVSSGGGGSEVQLVESGGGLVQAGGSLRLSCAASGRTFTMGWFR 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 RIDAADFDSWGQGTQVTVSSGGGGSEVQLVESGGGLVQAGGSLRLSCAASGRTFTMGWFR 180
Qy 181 QAPGKEREFVAAISLSPTLAYYAESVKGRFTISRDNAKNTVVLQMNSLKPEDTALYYCAA 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 QAPGKEREFVAAISLSPTLAYYAESVKGRFTISRDNAKNTVVLQMNSLKPEDTALYYCAA 240
Qy 241 DRKSVMSIRPDYWGQGTQVTVSSTSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAV 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 DRKSVMSIRPDYWGQGTQVTVSSTSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAV 300
Qy 301 HTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEED 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 HTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEED 360
Qy 361 GCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPE 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 GCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPE 420
Qy 421 MGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDAL 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 MGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDAL 480
Qy 481 HMQALPPR 488
||||||||
Db 481 HMQALPPR 488
Claim 4 is anticipated as the reference SEQ ID NO: 267 comprises the claimed GGGGS linker of SEQ ID NO: 3, see sequence italic and underline above.
Claim 6 is anticipated as the reference SEQ ID NO: 267 comprises the claimed CD8α comprises the amino acid sequence IYIWAPLAGTCGVLLLSLVITLYC which is identical to the claimed SEQ ID NO: 6, see sequence in red above.
Claim 8 is anticipated as the reference SEQ ID NO: 267 comprises the claimed co-stimulatory signal domain comprising the amino acid sequence KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL, which is identical to the claimed SEQ ID NO: 7 (see sequence in blue above) and intracellular signaling domain from CD3ζ comprises the rest of the amino acid sequence in magenta, see sequence above.
Claim 13 is anticipated as the reference SEQ ID NO: 267 comprises the claimed CD8α signaling peptide comprises MALPVTALLLPLALLLHAARP, which is identical to the claimed SEQ ID NO: 1, see reference SEQ ID NO: 267, sequence in bold and underline at the N-terminus, and the hinge domain, e.g., TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD located between the C-terminus of the extracellular domain and the N-terminus of the transmembrane domain, which is identical to the claimed SEQ ID NO: 5, see sequence in green above, in particular.
Regarding claim 18, Stirner teaches that the methods are for treating subjects with cancer, e.g., multiple myeloma, see para. [0003], refractory multiple myeloma, see para. [0072].
Regarding claim 22, Stirner teaches obtaining bone marrow aspirates from the subject having multiple myeloma and sequencing MRD-negative includes subjects that exhibit an absence of clonal plasma cells by NGS on bone marrow aspirate in which presence of a clone is defined as less than two identical sequencing reads obtained after DNA sequencing of bone marrow aspirates using the LymphoSIGHT platform (or validated equivalent method) with a minimum sensitivity of 1 in 105 nucleated cells or higher. In some aspect, imaging plus MRD-negative includes subjects that exhibit MRD negativity as assessed by NGS, see para. [0179].
Regarding claim 25, Stirner teaches that the subjects that have a MRD-negative disease include those exhibiting an absence of aberrant clonal plasma cells on bone marrow aspirate, ruled out by an assay with a minimum sensitivity of 1 in 105 nucleated cells or higher (i.e., 10-5 sensitivity), such as flow cytometry (next-generation flow cytometry; NGF) or high-throughput sequencing, e.g., deep sequencing or next-generation sequencing (NGS).
Regarding claim 28, Stirner teaches that the response to the therapy can be assessed over time after the initiation of administration of the cell therapy such as is at or about 1, 6, 12, or 24 months following initiation of administration, see p. 59, para. [0183]).
Regarding claim 29, Stirner teaches that the method of assessing responsiveness includes complete response (CR), stringent complete response (sCR), very good partial response (VGPR), see p. 58, para. [0182].
Regarding claim 30, Stirner teaches that 48% of the subject exhibiting a response better than VGPR. A complete response (CR) rate of 43% was observed in the lowest dose level of 5 x 107 total CAR- expressing T cells (DL1). Table E6 sets forth the results of minimal residual disease (MRD) assessment by next-generation sequencing (NGS), in 21 subjects in which MRD evaluation was possible. The assessment of response over time, in subjects in the DL1 cohorts at the longest follow-up, after administration of the CAR-expressing T cells (n = 14) is shown in FIG. 2. In general, response was observed to continue improve over time, with five (5) out of 14 subjects (36%) showing a deepening of response after day 29. Six (6) out of nine (9) subjects evaluated for MRD, were MRD negative (as assessed by NGS) at day 29, with one subject that had an MRD assessment at month 2, see para. [0725]. The expansion and long-term persistence of CAR+ T cells in the peripheral blood of subjects in the DL1, DL2, and DL3 cohorts are shown in FIG. 3. The results were consistent with a robust expansion of CAR+ T cells observed at all dose levels (DL1, DL2, and DL3). In general, an increased persistence past month 2 was observed in subjects administered a dose of ≥ 150 x 106 total CAR-expressing T cells (DL2 and DL3), see para. [0726]. The term “or” does not require determining that the subject is likely to have CR or sCR if the MRD negative status is maintained for longer than 6 months in the subject.
Regarding claim 32, Stirner teaches that the method of assessing responsiveness includes progression-free survival, see para.[0145], [0182].
Regarding claim 35, Stirner teaches that the assessment include duration of negative, e.g., MRD-negative at 5 years) response following administration of the cell, see para. [0181], [0180].
Regarding claims 36 and 37, Stirner teaches that the duration of response (DOR) includes the time from documentation of tumor response to disease progression. The parameter for assessing response can include durable response, e.g., response that persists after a period of time from initiation of therapy. In some embodiments, durable response is indicated by the response rate at approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18 or 24 months after initiation of therapy. In some embodiments, the response or outcome is durable for greater than at or about 3, 6, 9 or 12 months, see p. 60, para. [0185].
Thus, the reference teachings anticipate the claimed invention.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Stirner (WO2021207689 publication, published Oct 14, 2021; PTO 892) in view of Fan (WO2019001474 publication, published January 3, 2019; PTO 892).
The teachings of Stirner have been discussed supra.
Stirner does not teach the first VHH domain is at the C-terminus of the second VHH domain, optionally the first VHH domain comprises the amino acid sequence of SEQ ID NO: 4 and wherein the second VHH domain comprises the amino acid sequence of SEQ ID NO: 2.
However, Fan teaches a method of treating an induvial having multiple myeloma (claim 40-43) a chimeric antibody immune effector cell, e.g., human T cell (para. [0362]) expressing a bivalent BCMA-targeting antigen receptor (CAR) comprising the amino acid sequence of SEQ ID NO: 191, wherein the reference SEQ ID NO: 1 comprises the claimed SEQ ID NO: 4 fused to a linker of SEQ ID NO: 3 to a second VHH comprises the claimed SEQ ID NO: 2, see para. [0332], [0333], sequence alignment below, the sequence in bold corresponds to instant SEQ ID NO: 4, follows by linker GGGGS, then SEQ ID NO: 2:
Query Match 100.0%; Score 1246; Length 377;
Best Local Similarity 100.0%;
Matches 242; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQAGGSLRLSCAASGRTFTMGWFRQAPGKEREFVAAISLSPTLAYYAES 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQAGGSLRLSCAASGRTFTMGWFRQAPGKEREFVAAISLSPTLAYYAES 60
Qy 61 VKGRFTISRDNAKNTVVLQMNSLKPEDTALYYCAADRKSVMSIRPDYWGQGTQVTVSSGG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 VKGRFTISRDNAKNTVVLQMNSLKPEDTALYYCAADRKSVMSIRPDYWGQGTQVTVSSGG 120
Qy 121 GGSQVKLEESGGGLVQAGRSLRLSCAASEHTFSSHVMGWFRQAPGKERESVAVIGWRDIS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GGSQVKLEESGGGLVQAGRSLRLSCAASEHTFSSHVMGWFRQAPGKERESVAVIGWRDIS 180
Qy 181 TSYADSVKGRFTISRDNAKKTLYLQMNSLKPEDTAVYYCAARRIDAADFDSWGQGTQVTV 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 TSYADSVKGRFTISRDNAKKTLYLQMNSLKPEDTAVYYCAARRIDAADFDSWGQGTQVTV 240
Qy 241 SS 242
||
Db 241 SS 242
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the teachings of Stirner and Fan by substituting the bivalent VHH domain targeting chimeric antigen receptor of Sirner for Fan’s bivalent VHH domain targeting chimeric antigen receptor wherein the first VHH domain is at the C-terminus of the second VHH domain to arrive at the claimed invention with a reasonable expectation success, i.e., swapping the first VHH at the N-terminus with the second VHH located at the C-terminus is an obvious variation of the references teachings.
One of ordinary skill in the art would have been motivated to do so because Fan teaches that bivalent VHH BCMA-targeting antigen receptor (CAR) can be used for treating an induvial having multiple myeloma (claim 40-43) and Stirner teaches that duration response to bivalent VHH BCMA-targeting antigen receptor (CAR) can be assessed using next generation sequencing to determine whether the subject maintained minimal residual disease (MRD) for less than 6, at least 6 or at least 12 months.
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Claims 1, 33 and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Stirner (WO2021207689 publication, published Oct 14, 2021; PTO 892) in view of Berdeja et al (Lancet 398: 314-324, July 24, 2021; PTO 892).
The teachings of Stirner have been discussed supra.
Stirner does not teach the method determining that the subject is likely to have progression-free survival for at least 12 months post the treatment if the MRD negative status is maintained for longer than 6 months in the subject as per claim 33 or determining that the subject is likely to have progression-free survival for at least 24 months post the treatment if the MRD negative status is maintained for longer than 12 months in the subject as per claim 34.
However, Berdeja teaches a single infusion of Ciltacabtagene autoleucel (aka cilta-cel), a B-cell maturation antigen led to early, deep, and durable responses in patients with relapsed or refractory multiple myeloma. As evidenced in the specification at p. 68-69, Ciltacabtagene autoleucel comprises a VHH domain comprising the amino acid sequence set forth in SEQ ID NO: 2 and VHH domain comprising the amino acid sequence set forth in SEQ ID NO: 4, see para. [00247]. Berdeja teaches that nearly all patients (93%) who were evaluable for minimal residual disease at the 10-5 threshold achieved minimal residual disease negativity as early as a median of 1 month after cilta-cel treatment. Furthermore, 94% of patients with complete response or better who were evaluable for minimal residual disease achieved minimal residual disease 10-5 negativity. These results were achieved in patients with refractory disease who often have poor outcomes with each subsequent line of therapy and are considered challenging to treat. The rapidity and depth of response further suggest the potential of CAR T-cell therapies for changing the multiple myeloma disease course, see p. 319, Table 2, p. 321, discussion, in particular. 57 (59%) of 97 patients were evaluable for minimal residual disease at the 10-5 threshold; 40 (41%) of 97 were not evaluable primarily because of lack of an identifiable clone in the baseline bone marrow sample. Of 57 evaluable patients, 53 (93%) achieved minimal residual disease negativity (appendix p 19). Of 65 patients who achieved stringent complete response, 35 (54%) were evaluable for minimal residual disease assessment and 33 (94%) of 35 achieved minimal residual disease negativity at the 10-5 threshold. Median time to minimal residual disease negativity at 10-5 was 1·0 month (IQR 0·9–1·0). Median time to best response 2.6, (1.0 to 6.1). At the current median follow-up of 12·4 months in this study, the lower bound of the 95% CI for the 12-month progression-free survival rate is 66%, which might be a clinically meaningful improvement greater than that achieved with com parable anti-BCMA therapies in heavily pretreated patients with multiple myeloma, see p. 322, right col., in particular.
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine the teachings of Stirner and Berdeja to continue follow-up subjects treated with Ciltacabtagene autoleucel for progression-free survival for at least 12 months post treatment if the MRD negative status is maintained longer than 6 or 12 months to arrive at the claimed invention with a reasonable expectation success, i.e., Cilta-cel might be a viable treatment option for patients with relapsed or refractory multiple myeloma, with the highest overall response rate achieved to date in this heavily pretreated population.
One of ordinary skill in the art would have been motivated to do so because Berdeja teaches at a median follow-up of 12·4 months (IQR 10·6–15·2), overall response rate was 97% (95% CI 91·2–99·4; 94 of 97 patients), with 65 (67%) patients achieving stringent complete response (table 2). Median time to first response was 1·0 month (IQR 0·9–1·0), with 74 (79%) of 94 responders having their first response within 1·0 month of cilta-cel infusion. Median time to best response was 2·6 months (1·0–6·1). Median time to complete response or better was 1·9 months (1·0–6·5); 40 (62%) of 65 patients who achieved com plete response or better did so within 3·0 months of cilta-cel infusion. Responses deepened over time and were ongoing in 70 (72%) of 97 responders at the time of data cutoff (figure 2).
One of ordinary skill in the art would have been motivated to do so because Berdeja teaches that Cilta-cel is a structurally differentiated CAR T-cell therapy featuring two BCMA-targeting single-domain antibodies designed to confer avidity. Cilta-cel showed unprecedented clinical activity compared with other novel anti-myeloma treatments in comparable study populations, see p. 321, right col.
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
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 1-4, 6, 8, 13, 17-18, 22, 25, 28-30 and 32-37 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, 41, 57, 59, 82, 84, 85, 90, 110, 122 of copending Application No. 18/039,420. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of Appl. 420 recites:
(Currently Amended) A method of treating a subject who has multiple myeloma, the method comprising administering to the subject via a single intravenous infusion a composition comprising T cells comprising a chimeric antigen receptor (CAR) comprising: a) an extracellular antigen binding domain comprising a first BCMA binding moiety and a second BCMA binding moiety; b) a transmembrane domain; and c) an intracellular signaling domain, to deliver to the subject a dose of CAR expressing T cells (CAR-T cells), wherein the first BCMA binding moiety comprises the amino acid sequence set forth in SEQ ID NO: 2 and the second BCMA binding moiety comprises the amino acid sequence set forth in SEQ ID NO: 4, which correspond to instant claims 1, 2, 3.
10. (Currently Amended) The method of claim 1, wherein said method is effective in obtaining minimal residual disease (MRD) negative status in said subject assessed in the bone marrow after said infusion of said CAR-T cells, wherein optionally said MRD negative status is obtained at a first follow-up time of between approximately 28 days and approximately 179 days after said infusion of said CAR-T cells, and wherein optionally:(1) said method is effective in obtaining said MRD negative status at:(i) a rate of between approximately 44% and approximately 65% at a sensitivity threshold level of 10-5 at a follow-up time of approximately 12 months after said infusion of said CAR-T cells; (ii) a rate of between approximately 57% and approximately 76% at a sensitivity threshold level of 10-4 at a follow-up time of approximately 18 months after said infusion of said CAR-T cells; (iii) a rate of between approximately 47% and approximately 68% at a sensitivity threshold level of 10-5 at a follow-up time of approximately 18 months after said infusion of said CAR-T cells; or (iv) a rate of between approximately 29% and approximately 50% at a sensitivity threshold level of 10-6 at a follow-up time of approximately 18 months after said infusion of said CAR-T cells; (2) said method is effective in obtaining said MRD negative status at:(i) a rate of approximately 55% at a sensitivity threshold level of 10-5 at a follow-up time of approximately 12 months after said administration of said CAR-T cells; filed December 21, 2023 (ii) a rate of approximately 67% at a sensitivity threshold level of 10-4 at a follow-up time of approximately 18 months after said infusion of said CAR-T cells; (iii) a rate of approximately 58% at a sensitivity threshold level of 10-5 at a follow-up time of approximately 18 months after said infusion of said CAR-T cells; or (iv) a rate of approximately 39% at a sensitivity threshold level of 10-6 at a follow-up time of approximately 18 months after said infusion of said CAR-T cells; (3) said method is effective in obtaining said minimal residual disease (MRD) negative status at a rate of between approximately 83% and approximately 98% in subjects with evaluable samples at a sensitivity threshold level of 10-5 at a follow-up time of approximately 12 months after said infusion of said CAR-T cells, or at a rate of between approximately 82% and approximately 97% in subjects with evaluable samples at a sensitivity threshold level of 10-5 at a follow-up time of approximately 18 months after said infusion of said CAR-T cells; or (4) said method is effective in obtaining said minimal residual disease (MRD) negative status at a rate of approximately 93% in subjects with evaluable samples at a sensitivity threshold level of 10-5 at a follow-up time of approximately 12 months after said infusion of said CAR-T cells, or at a rate of approximately 92% in subjects with evaluable samples at a sensitivity threshold level of 10-5 at a follow-up time of approximately 18 months after said infusion of said CAR-T cells, which corresponds to instant claims 1, 25, 33-34.
59. (Currently Amended) The method of claim 1, wherein:
(1) the first BCMA binding moiety and/or the second BCMA binding moiety is an anti- BCMA VHH, wherein optionally the first BCMA binding moiety is a first anti-BCMA VHH and the second BCMA binding moiety is a second anti-BCMA VHH;
(2) the first BCMA binding moiety comprises a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 10;
(3) the second BCMA binding moiety comprises a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 12;
(4) the first BCMA binding moiety and the second BCMA binding moiety are connected to each other via a peptide linker, wherein optionally the peptide linker comprises the amino acid sequence of SEQ ID NO: 3, wherein further optionally the peptide linker comprises a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 11;
(5) the CAR polypeptide further comprises a signal peptide located at the N-terminus of the polypeptide, wherein optionally the signal peptide is derived from CD8-alpha, wherein further optionally the signal peptide comprises the amino acid sequence of SEQ ID NO: 1, and wherein further optionally the signal peptide comprises a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 9;
(6) the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 6;
(7) the transmembrane domain comprises a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 14;
(8) the intracellular signaling domain comprises a primary intracellular signaling domain of an immune effector cell;
(9) the intracellular signaling domain is derived from CD3;
(10) the intracellular signaling domain comprises one or more co-stimulatory signaling domains, wherein optionally the intracellular signaling domain comprises the amino acid sequence of SEQ ID NO: 8, wherein optionally the intracellular signaling domain comprises a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 16, wherein optionally the intracellular signaling domain comprises the amino acid sequence of SEQ ID NO: 7, and wherein optionally the intracellular signaling domain comprises a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 15; or
(11) the CAR polypeptide further comprises a hinge domain located between the C- terminus of the extracellular antigen binding domain and the N-terminus of the transmembrane domain, wherein optionally the hinge domain comprises the amino acid sequence of SEQ ID NO: 5, and wherein optionally the hinge domain comprises a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 13, which correspond to instant claims 1, 2, 3, 4, 6, 8, 13.
84. (Currently Amended) The method of claim 1, wherein the subject is human.
85. (Original) A method of treating a subject who has multiple myeloma and received at least three prior lines of treatment, the method comprising administering to the subject via a single intravenous infusion a composition comprising T cells comprising a chimeric antigen receptor (CAR) comprising the amino acid sequence of SEQ ID NO: 17 to deliver to the subject a dose of approximately 0.75 x 106 CAR expressing T cells (CAR-T cells) per kilogram of the mass of the subject, wherein said method is effective in obtaining minimal residual disease (MRD) negative status in said subject assessed in the bone marrow at a follow-up time of greater than or equal to 28 days following said infusion of said CAR-T cells, which corresponds to instant claims 17, 25.
90. (Currently Amended) The method of claim 1, wherein said method is effective in obtaining at least one response in the subject after said infusion of said CAR-T cells, wherein said at least one response comprises, in order from better to worse:
(i) a stringent complete response;
(ii) a complete response;
(iii) a very good partial response;
(iv) a partial response; or
(v) a minimal response; wherein optionally:
(a) said method is effective in obtaining a first response before a time of between approximately 27 days and approximately 321 days after said infusion of said CAR-T cells, wherein further optionally said method is effective in obtaining a first response before a time of between approximately 27 days and approximately 89 days after said infusion of said CAR-T cells, wherein further optionally said method is effective in obtaining a first response before approximately 42 days after said infusion of said CAR- T cells, wherein further optionally said method is effective in obtaining a first response before approximately 29 days after said infusion of said CAR-T cells;
(b) said method is effective in obtaining a best response of any one of minimal response, partial response, very good partial response, complete response or stringent complete response, wherein further optionally wherein said method is effective in obtaining said best response of any one of minimal response, partial response, very good partial response, complete response or stringent complete response at a rate of between approximately 91% and approximately 99% at a follow-up time of approximately 12 months after said infusion of said CAR-T cells or at a rate of between approximately 93% and approximately 100% at a follow-up time of approximately 18 months after said infusion of said CAR-T cells, and wherein further optionally wherein said method is effective in obtaining said best response of any one of minimal response, partial response, very good partial response, complete response or stringent complete response at a rate of approximately 97% at a follow-up time of approximately 12 months after said infusion of said CAR-T cells or at a rate of approximately 98% at a follow-up time of approximately 18 months after said infusion of said CAR-T cells;
(c) said method is effective in obtaining a best response of any one of partial response, very good partial response, complete response or stringent complete response, wherein further optionally said method is effective in obtaining said best response of any one of partial response, very good partial response, complete response or stringent complete response at a rate of between approximately 91% and approximately 99% at a follow-up time of approximately 12 months after said infusion of said CAR-T cells or at a rate of between approximately 93% and approximately 100% at a follow-up time of approximately 18 months after said infusion of said CAR-T cells, and wherein further optionally said method is effective in obtaining said best response of any one of partial response, very good partial response, complete response or stringent complete response at a rate of approximately 97% at a follow-up time of approximately 12 months after said infusion of said CAR-T cells or at a rate of approximately 97% at a follow-up time of approximately 18 months after said infusion of said CAR-T cells; (d) said method is effective in obtaining a best response of any one of very good partial response, complete response or stringent complete response, wherein further optionally said method is effective in obtaining said best response of any one of very good partial response, complete response or stringent complete response at a rate of between approximately 86% and approximately 97% at a follow-up time of approximately 12 months after said infusion of said CAR-T cells or at a rate of between approximately 88% and approximately 98% at a follow-up time of approximately 18 months after said infusion of said CAR-T cells, wherein further optionally said method is effective in obtaining said best response of any one of very good partial response, complete response or stringent complete response at a rate of approximately 93% at a follow-up time of approximately 12 months after said infusion of said CAR-T cells or at a rate of approximately 95% at a follow-up time of approximately 18 months after said infusion of said CAR-T cells; (e) said method is effective in obtaining a best response of complete response or stringent complete response, wherein further optionally said method is effective in obtaining said best response of complete response or stringent complete response at a rate of between approximately 57% and approximately 76% at a follow-up time of approximately 12 months after said infusion of said CAR-T cells or at a rate of between approximately 73% and approximately 89% at a follow-up time of approximately 18 months after said infusion of said CAR-T cells, wherein further optionally said method is effective in obtaining said best response of complete response or stringent complete response at a rate of approximately 67% at a follow-up time of approximately 12 months after said infusion of said CAR-T cells or at a rate of approximately 83% at a follow-up time of approximately 18 months after said infusion of said CAR-T cells; or (f) said method is effective in obtaining a best response of stringent complete response, wherein further optionally said method is effective in obtaining said best response of stringent complete response at a rate of between approximately 57% and approximately 76% at a follow-up time of approximately 12 months after said infusion of said CAR-T cells or at a rate of between approximately 73% and approximately 89% at a follow-up time of approximately 18 months after said infusion of said CAR-T cells, wherein further optionally said method is effective in obtaining said best response of stringent complete response at a rate of approximately 67% at a follow-up time of approximately 12 months after said infusion of said CAR-T cells or at a rate of approximately 83% at a follow-up time of approximately 18 months after said infusion of said CAR-T cells; and wherein further optionally:(1) said method is effective in obtaining said best response before a time of between approximately 27 days and approximately 534 days after said infusion of said CAR-T filed December 21, 2023 cells or between approximately 27 days and approximately 293 days after said infusion of said CAR-T cells; or (2) said method is effective in obtaining said best response before approximately 153 days after said infusion of said CAR-T cells or before approximately 78 days after said infusion of said CAR-T cells, which corresponds to instant claim 29, 30.
110. (Currently Amended) The method of claim 1, wherein said method is effective in obtaining progression-free survival of the subject, wherein optionally:(1) said method is effective in obtaining said progression-free survival of the subject at a time between said infusion of said CAR-T cells and:(i) approximately 209 days after said infusion of said CAR-T cells; (ii) approximately 386 days after said infusion of said CAR-T cells; (iii) approximately 632 days after said infusion of said CAR-T cells; or (iv) approximately 684 days after said infusion of said CAR-T cells; (2) said method is effective in obtaining said progression-free survival at:(i) a rate of between approximately 79% and approximately 93% at a follow- up time of approximately 6 months after said infusion of said CAR-T cells; (ii) a rate of between approximately 67% and approximately 84% at a follow- up time of approximately 12 months after said infusion of said CAR-T cells; (iii) a rate of between approximately 57% and approximately 75% at a follow- up time of approximately 18 months after said infusion of said CAR-T cells; (iv) a rate of between approximately 57% and approximately 75% at a follow- up time of approximately 21 months after said infusion of said CAR-T cells; or (v) a rate of between approximately 49% and approximately 70% at a follow- up time of approximately 24 months after said infusion of said CAR-T cells; or (3) said method is effective in obtaining said progression-free survival at: (i) a rate of approximately 88% at a follow-up time of approximately 6 months after said infusion of said CAR-T cells; filed December 21, 2023 (ii) a rate of approximately 76% at a follow-up time of approximately 12 months after said infusion of said CAR-T cells; (iii) a rate of approximately 67% at a follow-up time of approximately 18 months after said infusion of said CAR-T cells; (iv) a rate of approximately 67% at a follow-up time of approximately 21 months after said infusion of said CAR-T cells; or (v) a rate of approximately 61% at a follow-up time of approximately 24 months after said infusion of said CAR-T cells, which corresponds to instant claims 32-34.
122. (Currently Amended) The method of claim 90, wherein:
(1)said method is effective in maintaining a response in the subject at a follow-up time between the time of said first response and:
(i) approximately 180 days after said infusion of said CAR-T cells; (ii approximately 357 days after said infusion of said CAR-T cells;
(iii) approximately 606 days after said infusion of said CAR-T cells; or
(iv) approximately 654 days after said infusion of said CAR-T cells;
(2) said method is effective in maintaining a response at:
(i) a rate of between approximately 77% and approximately 91% at a follow-up time of approximately 6 months after said infusion of said CAR-T cells;
(ii) a rate of between approximately 63% and approximately 81% at a follow-up time of approximately 12 months after said infusion of said CAR-T cells;
(iii) a rate of between approximately 56% and approximately 75% at a follow-up time of approximately 18 months after said infusion of said CAR-T cells;
(iv) a rate of between approximately 52% and approximately 72% at a follow-up time of approximately 21 months after said infusion of said CAR-T cells; or
(v) a rate of between approximately 48% and approximately 70% at a follow-up time of approximately 24 months after said infusion of said CAR-T cells; or
(3) said method is effective in maintaining a response at: (i) a rate of approximately 85% at a follow-up time of approximately 6 months after said infusion of said CAR-T cells; (ii) a rate of approximately 74% at a follow-up time of approximately 12 months after said infusion of said CAR-T cells; (iii) a rate of approximately 67% at a follow-up time of approximately 18 months after said infusion of said CAR-T cells; (iv) a rate of approximately 63% at a follow-up time of approximately 21 months after said infusion of said CAR-T cells; or (v) a rate of approximately 60% at a follow-up time of approximately 24 months after said infusion of said CAR-T cells; and wherein optionally said method is effective in obtaining minimal residual disease (MRD) negative status in said subject assessed in the bone marrow at a sensitivity threshold level of 10-5 between the time of said administration of said CAR-T cells and approximately 3 months after said administration of said CAR-T cells, wherein further optionally said method is effective in obtaining either MRD negative complete response or MRD negative stringent complete response at a rate of between approximately 25% and approximately 44% at a follow-up time of filed December 21, 2023 approximately 12 months after said infusion of said CAR-T cells or at a rate of between approximately 33% and approximately 54% at a follow-up time of approximately 18 months after said infusion of said CAR-T cells, wherein further optionally said method is effective in obtaining either minimal residual disease (MRD) negative complete response or minimal residual disease (MRD) negative stringent complete response at a rate of approximately 34% at a follow-up time of approximately 12 months after said infusion of said CAR-T cells or at a rate of approximately 43% at a follow-up time of approximately 18 months after said infusion of said CAR-T cells, which correspond to instant claims 35-37.
18/499,720
18/039,420
SEQ ID NO: 1
MALPVTALLLPLALLLHAARP
MALPVTALLLPLALLLHAARP
First VHH
SEQ ID NO: 2
SEQ ID NO: 2
SEQ ID NO: 3 linker
GGGGS
GGGGS
Second VHH
SEQ ID NO: 4
SEQ ID NO: 4
CD8a hinge
SEQ ID NO: 5
SEQ ID NO: 5
CD8a transmembrane
SEQ ID NO: 6
SEQ ID NO: 6
CD137 cytoplasmic
SEQ ID NO: 7
SEQ ID NO: 7
CD3zeta
SEQ ID NO: 8
SEQ ID NO: 8
Ciltacabtagene autoleucel CAR
SEQ NO: 17
SEQ ID NO: 17
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Claims 1-4, 6, 8, 13, 17-18, 22, 25, 28-30 and 32-37 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 40, 45, 47, 49, 76, 81 and 116 of copending Application No. 19/045,249. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of Appl. 249 recites:
(Original) A method of treating a subject with multiple myeloma, wherein the subject has not achieved a complete response after receiving an initial therapy comprising a stem cell transplantation, the method comprising administering to the subject a dose of T cells comprising a chimeric antigen receptor (CAR) comprising:(a) an extracellular antigen binding domain capable of specifically binding to an epitope of B-cell maturation antigen (BCMA), wherein the extracellular antigen binding domain comprises a first VHH domain and a second VHH domain, and wherein the first VHH domain comprising a CDR1, a CDR2, and a CDR3 as set forth in the VHH domain comprising the amino acid sequence of SEQ ID NO: 2, and the second VHH domain comprising a CDR1, a CDR2, and a CDR3 as set forth in the VHH domain comprising the amino acid sequence of SEQ ID NO: 4,(b) a transmembrane domain, and(c) an intracellular signaling domain, which corresponds to instant claim 1(a), 2.
40. (Currently Amended) The method of claim1, wherein the method is effective in obtaining minimal residual disease (MRD) negativity assessed in the bone marrow of the subject after the administering to the subject the dose of the T cells, wherein optionally (a) the MRD negativity is assessed using next generation sequencing (NGS) or next generation flow (NGF) on bone marrow aspirate DNA of the subject, wherein optionally the MRD negativity is assessed at a sensitivity of 10-5, and/or (b) the method is effective in obtaining MRD negativity at about 0.9 month to about 6.1 months after the administering to the subject the dose of the T cells, further wherein optionally (i) the method is effective in obtaining MRD negativity at a median time of about 1.33 months after the administering to the subject the dose of the T cells, or (ii) the method is effective in obtaining MRD negativity at a mean time of about 2.10 months after the administering to the subject the dose of the T cells, which corresponds to instant claims 1(b) to (c), 2, 3, 4, 25.
45. The method of claim 40, wherein the method is effective in obtaining the MRD negativity at a rate of between about 44.0% to about 89.7% at a sensitivity of 10-5, wherein optionally the method is effective in obtaining the MRD negativity at a rate of about 70.6% at a sensitivity of 10-5, which corresponds to instant claim 25.
47. (Currently Amended) The method of claim 40, wherein the method is effective in obtaining the MRD negativity at a rate of between about 51.9% to about 95.7% at a sensitivity of 10-5, wherein optionally the method is effective in obtaining the MRD negativity at a rate of about 80.0% at a sensitivity of 10-5.
49. (Currently Amended) The method of claim1, wherein the method is effective in obtaining at least one response in the subject after the administering to the subject the dose of the T cells, and wherein the at least one response comprises, in order from better to worse:
(i) a stringent complete response;
(ii) a complete response;
(iii) a very good partial response;
(iv) a partial response; or
(v) a minimal response, wherein optionally
(a) the method is effective in obtaining a first response of any one of a partial response, a very good partial response, a complete response, or a stringent complete response, further wherein optionally the method is effective in obtaining the first response at a time of between about 0.9 months and about 12.5 months after the administering of the dose of the T cells, and further wherein optionally
(i) the method is effective in obtaining the first response at a mean time of about 3.07 months after the administering of the dose of the T cells, or
(ii) the method is effective in obtaining a first response at a median time of about 1.30 months after the administering of the dose of the T cells,
(b) the method is effective in obtaining a best response of any one of a partial response, a very good partial response, a complete response, or a stringent complete response, further wherein optionally the method is effective in obtaining the best response at a time of between about 0.9 months and about 12.5 months after the administering of the dose of the T cells, and further wherein optionally
(i) the method is effective in obtaining the best response at a mean time of about 4.02 months after the administering of the dose of the T cells, or
(ii) the method is effective in obtaining the best response at a median time of about 1.89 months after the administering of the dose of the T cells, (c) the method is effective in obtaining a complete response or a stringent complete response at a time of between about 0.9 months and about 12.5 months after the administering of the dose of the T cells, further wherein optionally (i) the method is effective in obtaining the complete response or the stringent complete response at a mean time of about 3.30 months after the administering of the dose of the T cells, or (ii) the method is effective in obtaining the complete response or the stringent complete response at a median time of about 1.72 months after the administering of the dose of the T cells, (d) the method is effective in obtaining a complete response or a stringent complete response at a rate of between about 71.3% and about 99.9%, further wherein optionally the method is effective in obtaining the complete response or the stringent complete response at a rate of about 94.1%, (e) the method is effective in obtaining a very good partial response, a complete response or a stringent complete response at a rate of between about 71.3% and about 99.9%, further wherein optionally the method is effective in obtaining the very good partial response, the complete response or the stringent complete response at a rate of about 94.1%, (f) the method is effective in obtaining a partial response, a very good partial response, a complete response or a stringent complete response at a rate of between about 71.3% and about 99.9%, further wherein optionally the method is effective in obtaining the partial response, the very good partial response, the complete response or the stringent complete response at a rate of about 94.1%, (g) the method is effective in obtaining a minimal response, a partial response, a very good partial response, a complete response or a stringent complete response at a rate of between about 71.3% and about 99.9%, further wherein optionally the method is effective in obtaining the minimal response, the partial response, the very good partial response, the complete response or the stringent complete response at a rate of about 94.1%,(h) the method is effective in obtaining a best response comprising a stringent complete response at a rate of between about 63.6% and about 98.5%, further wherein optionally the method is effective in obtaining the stringent complete response at a rate of about 88.2%,(i) the method is effective in obtaining a best response comprising a complete response or a stringent complete response and further comprising a MRD negativity at a rate of between about 50.1% and about 93.2%, wherein optionally the method is effective in obtaining the best response at a rate of about 76.5%,(j) the method is effective in obtaining a best response comprising a complete response at a rate of between about 0.1% and about 28.7%, wherein optionally the method is effective in obtaining the best response at a rate of about 5.9%, or (k) the method is effective in maintaining the response for at least about 6 months at a rate of about 100%, further wherein optionally the method is effective in maintaining the response for at least about 9 months or about 12 months at a rate of about 100%, which corresponds to instant claim 25, 29, 30.
76. (Currently Amended) The method of claim1, wherein the method is effective in obtaining progression-free survival of the subject wherein optionally the method is effective in obtaining the progression-free survival at a rate of about 100.0% at a follow-up time of about 6 months or about 9 months, or wherein optionally the method is effective in obtaining the progression-free survival at a rate of between about 63.2% and about 99.1% at a follow-up time of about 12 months or about 18 months, wherein optionally the method is effective in obtaining the progression-free survival at a rate of about 93.8% at a follow-up time of about 12 months or about 18 months, which corresponds to instant claims 32-34.
81. (Currently Amended) The method of claim1, wherein the method is effective in obtaining an overall survival rate, wherein optionally the overall survival rate is about 100.0% at a follow-up time of about 6 months or about 9 months, or wherein optionally the overall survival rate is between about 63.2% and about 99.1% at a follow-up time of about 12 months or about 18 months, wherein optionally the overall survival rate is about 93.8% at a follow-up time of about 12 months or about 18 months, which corresponds to instant claim 34.
116. (Currently Amended) The method of claim 1, wherein the first VHH domain comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 18, a CDR2 comprising the amino acid sequence of SEQ ID NO: 19, a CDR3 comprising the amino acid sequence of SEQ ID NO: 20, and
the second VHH domain comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 21, a CDR2 comprising the amino acid sequence of SEQ ID NO: 22, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 23,
wherein optionally the first VHH domain comprises the amino acid sequence of SEQ ID NO: 2 and the second VHH domain comprises the amino acid sequence of SEQ ID NO: 4,
wherein optionally the first VHH domain is at the N-terminus of the second VHH domain, or the first VHH domain is at the C-terminus of the second VHH domain, further wherein optionally:
(a) the first VHH domain is linked to the second VHH domain via a linker, wherein optionally the linker comprises the amino acid sequence of SEQ ID NO: 3;
(b) the transmembrane domain is derived from a molecule selected from the group consisting of CD8a, CD4, CD28, CD137, CD80, CD86, CD152 and PD1, wherein optionally the transmembrane domain is derived from CD8a, wherein optionally the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 6;
(c) the intracellular signaling domain comprises a primary intracellular signaling domain of an immune effector cell, wherein optionally the primary intracellular signaling domain is derived from CD3ζ, wherein optionally the primary intracellular signaling domain comprises the amino acid sequence of SEQ ID NO: 8;
(d) the intracellular signaling domain comprises a co-stimulatory signaling domain, wherein optionally the co-stimulatory signaling domain is derived from a co-stimulatory molecule selected from the group consisting of CD27, CD28, CD137, OX40, CD30, CD40, CD3, LFA-1, ICOS, CD2, CD7, LIGHT, NKG2C, B7-H3, ligands of CD83 and any combination thereof, wherein optionally the co-stimulatory signaling domain comprises a cytoplasmic domain of CD 137, wherein optionally the co-stimulatory signaling domain comprises the amino acid sequence of SEQ ID NO: 7;
(e) the CAR further comprises a hinge domain located between the C-terminus of the extracellular antigen binding domain and the N-terminus of the transmembrane domain, wherein optionally the hinge domain is derived from CD8a, wherein optionally the hinge domain comprises the amino acid sequence of SEQ ID NO: 5;
(f) the CAR further comprises a signal peptide located at the N-terminus of the polypeptide, wherein optionally the signal peptide is derived from CD8a comprising the amino acid sequence of SEQ ID NO: 1; or (g) the CAR comprises the amino acid sequence of SEQ ID NO: 17, which corresponds to instant claims 1, 2, 3, 4, 6, 8, 13 and 17.
18/499,720
19/045,247
SEQ ID NO: 1
MALPVTALLLPLALLLHAARP
MALPVTALLLPLALLLHAARP
First VHH
SEQ ID NO: 2
SEQ ID NO: 2
SEQ ID NO: 3 linker
GGGGS
GGGGS
Second VHH
SEQ ID NO: 4
SEQ ID NO: 4
CD8a hinge
SEQ ID NO: 5
SEQ ID NO: 5
CD8a transmembrane
SEQ ID NO: 6
SEQ ID NO: 6
CD137 cytoplasmic
SEQ ID NO: 7
SEQ ID NO: 7
CD3zeta
SEQ ID NO: 8
SEQ ID NO: 8
Ciltacabtagene autoleucel CAR
SEQ NO: 17
SEQ ID NO: 17
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
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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