DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
1. Applicant’s election without traverse of SEQ ID NO: 37 and the DOTA hapten having the structure
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in the reply filed on 12/12/2025 is acknowledged.
Claims 2-5, 7-12, 14, 17-23, 25-28, 31, 32, 35-41, 44-46, 48-50, 52-54, 56, 58-
64, 66, 68, 69, and 72-75 have been cancelled.
Claims 1, 6, 13, 15, 16, 24, 29, 30, 33, 34, 42, 43, 47, 51, 55, 57, 65, 67, 70, and
71 are pending and under examination.
2. Below is a non-binding, courtesy suggestion to redraft your independent claims 55, 65, and 67 in a clearer, more reader-friendly manner. Based on a plain reading, the claim appears to inform with reasonable certainty and thus is not indefinite under 35 U.S.C. 112(b). That said, modest edits will improve public readability, reduce the risk of misinterpretation, and align with drafting practices favored by the MPEP (see MPEP 2173 on clarity/definiteness and MPEP 2111 on broadest reasonable interpretation).
Claim 55
A method for detecting tumors in a subject in need thereof comprising
(I)
(a) administering to the subject an effective amount of a complex comprising the engineered immune cell of claim 1 and a radiolabeled-DOTA hapten configured to bind to the anti-DOTA C825 antigen binding fragment expressed by the engineered immune cell, wherein the target antigen recognized by the engineered immune cell is a tumor antigen and wherein the complex localizes to the tumors expressing the tumor antigen; and
(b) detecting the presence of the tumors in the subject by detecting radioactive levels emitted by the complex that are higher than a reference value; or
(II)
(a) administering to the subject an effective amount of the engineered immune cells of claim 1, wherein the target antigen recognized by the engineered immune cells is a tumor antigen and wherein the engineered immune cells localize to the tumors expressing the tumor antigen;
(b) administering to the subject an effective amount of a radiolabeled- DOTA hapten, wherein the radiolabeled-DOTA hapten is configured to bind to the anti-DOTA C825 antigen binding fragment expressed by the engineered immune cells; and
(c) detecting the presence of the tumors in the subject by detecting radioactive levels emitted by the radiolabeled-DOTA hapten that are higher than a reference value.
Claim 65
A method for monitoring biodistribution of engineered immune cells in a subject comprising:
I
(a) administering to the subject an effective amount of the engineered immune cells of claim 1, wherein the engineered immune cells localize to a tissue expressing the target antigen recognized by the engineered immune cells;
(b) administering to the subject an effective amount of a radiolabeled- DOTA hapten configured to bind to the anti-DOTA C825 antigen binding fragment expressed by the engineered immune cell; and
(c) determining the biodistribution of the engineered immune cells in the subject by detecting radioactive levels emitted by the radiolabeled-DOTA hapten that are higher than a reference value:
or
(II)
(a) administering to the subject an effective amount of a complex comprising the engineered immune cell of claim 1 and a radiolabeled-DOTA hapten configured to bind to the anti-DOTA C825 antigen binding fragment expressed by the engineered immune cell, wherein the complex localizes to a tissue expressing the target antigen recognized by the engineered immune cells; and
(b) determining the biodistribution of the engineered immune cells in the subject by detecting radioactive levels emitted by the radiolabeled-DOTA hapten that are higher than a reference value.
Claim 67
A method for monitoring viability of engineered immune cells in a subject comprising:
I
(a) administering to the subject an effective amount of the engineered immune cells of claim 1, wherein the target antigen recognized by the engineered immune cells is a tumor antigen and wherein the engineered immune cells localize to the tumors expressing the tumor antigen;
(b) administering to the subject an effective amount of a radiolabeled- DOTA hapten, wherein the radiolabeled-DOTA hapten is configured to bind to the anti-DOTA C825 antigen binding fragment expressed by the engineered immune cells;
(c) detecting radioactive levels emitted by the radiolabeled-DOTA hapten that are higher than a reference value at a first time point;
(d) detecting radioactive levels emitted by the radiolabeled-DOTA hapten that are higher than a reference value at a second time point; and
(e) determining that the engineered immune cells in the subject are viable when the radioactive levels emitted by the radiolabeled-DOTA hapten at the second time point are comparable to that observed at the first time point, optionally wherein the method further comprises administering to the subject a second effective amount of the radiolabeled-DOTA hapten prior to step (d);
or
(II)
(a) administering to the subject an effective amount of a complex comprising the engineered immune cell of claim 1 and a radiolabeled-DOTA hapten configured to bind to the anti-DOTA C825 antigen binding fragment expressed by the engineered immune cell, wherein the target antigen recognized by the engineered immune cell is a tumor antigen and wherein the complex localizes to the tumors expressing the tumor antigen;
(b) detecting radioactive levels emitted by the radiolabeled-DOTA hapten that are higher than a reference value at a first time point;
(c) detecting radioactive levels emitted by the radiolabeled-DOTA hapten that are higher than a reference value at a second time point; and
(d) determining that the engineered immune cells in the subject are viable when the radioactive levels emitted by the radiolabeled-DOTA hapten at the second time point are comparable to that observed at the first time point.
Claim Objections
3. Claim1 is objected to because of the recitation that the anti-DOPA C825 antigen binding fragment comprises SEQ ID NOs: 37-39, 40, or 41.
The anti-DOPA C825 antigen binding fragment consists of (i.e., does not comprise) the amino acid sequence set forth by SEQ ID NOs: 37 or 38 (see the specification, [0106]).
The anti-DOPA C825 antigen binding fragment does not comprise SEQ ID NOs: 39, 40, and 41. Rather, SEQ ID NOs: 39, 40, and 41 comprise the anti-DOPA C825 antigen binding fragment (see the specification, [0109], [0111], and Fig. 3B-C).
It is suggested that the recitation “an anti-DOPA C825 antigen binding fragment comprising the amino acid sequence of any one of SEQ ID NOs: 35-39, 40, and 41” be replaced with “an anti-DOPA C825 antigen binding fragment comprising the amino acid sequence set forth by any of SEQ ID NO: 35 and 36 or consisting of the amino acid sequence set forth by any of SEQ ID NOs: 37 and 38”.
4. Claim 51 is objected to because of the recitation “a lone pair of electrons (i.e., providing an oxygen anion)”. Correction to “a lone pair of electrons providing an oxygen anion” is suggested.
5. Claim 57 is objected to because of the recitation “between a tumor” in line 9. Correction to “between the tumors” is suggested.
Claim Rejections - 35 USC § 112(b)
6. 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.
7. Claims 55, 57, 65, 67, 70, and 71 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Specifically, the recitation “a reference value” renders claims 55, 65, 67, and 70 unclear because the reference value to which radioactivity is compared is not defined by the claims and specification. The recitation “a reference value” is reasonably interpreted as meaning a specific radioactive level to which the results are compared. Neither the claims nor the specification define what this specific radioactive level is. The specification discloses that the reference value may be obtained by averaging the radioactive level in normal tissues or it may be the standardized uptake value (SUV) (see [0263]); however, this does not define what the reference value per se is. Averaging radioactivity in normal tissues and determining SUV are different methods resulting in different reference values (see Mah et al., Biological Target Volume, 2008, Abstract). Thus, higher radioactivity is measured in relation to an object that is variable, which renders the claims indefinite. See also MPEP 2173.05(b) II.
Claims 57 and 71 are rejected for being dependent from the rejected claims 55 and 65, respectively, and also for failing to further clarify the basis of the rejection.
Claim Rejections - 35 USC § 103
8. 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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
9. Claims 1, 6, 13, 15, 16, 24, 29, 30, 33, 34, 42, 43, 47, 51, 55, 57, 65, and 71 are rejected under 35 U.S.C. 103 as being unpatentable over Krebs et al. (J. Nucl. Med., 2018, 59: 1894-1900), in view of both Cheal et al. (WO 19/010299) and Powell et al. (WO 20/219715). Cheal and Powell are cited on the IDS filed on 12/28/2022.
Krebs et al. teach engineered T-cells expressing a CD19 CAR and an anti-DOTA scFv anchored at the cell surface via the transmembrane domain (TM) of CD4. The CD19 CAR comprises an anti-CD19 scFv as extracellular domain, the CD28 TM, and an intracellular domain containing CD3zeta signaling and CD28 costimulatory domains. The anti-DOTA scFv has the antigen binding fragment of the monoclonal antibody 2D12.5; it further comprises the G54C substitution leading to its irreversible binding (infinite binder) to the 86Y-radiolabeled hapten acrylamidobenzoyl-DOTA (86Y-AABD).
Krebs et al. teach using scFv 2D12.5 as a reporter for in vivo tracking the accumulation of the engineered T-cells within tumors. Krebs et al. teach administering the engineered T-cells to tumor-carrying subjects, followed by the intravenous administration of 86Y-AABD and imaging via positron emission tomography (PET) to detect the accumulation of the 86Y-AABD/T-cell complexes within tumors (claims 1, 13, 15, 16, and 24) (see Abstract; p. 1895; p. 1896, column 1 and Fig. 3; p. 1898, column 2, last paragraph and Fig. 5; p. 1899, column 1, p. 1900, column 1, second paragraph).
Krebs et al. do not teach an scFv having the antigen binding fragment of the monoclonal antibody C825 (claim 1). Cheal et al. that both scFv 2D12.5 and scFv C825 bind DOTA, both are suitable to be used in PET imaging, and both could be used either as wild-type or as G54C mutants (infinite binders) (see [0012]; [0083]). Thus, modifying Krebs et al. by using anti-DOTA C825 scFv would have been obvious to one of skill in the art to achieve the predictable result of obtaining genetically engineered T-cells expressing on their surface a reporter enabling tracking in vivo.
Furthermore, Cheal et al. teach that, while conventional DOTA haptens are suitable for radiotherapy with beta particles emitting isotopes (such as 86Y), they are not suitable for applications requiring radiotherapy with alpha particle-emitting isotopes such as treating solid tumors. Cheal et al. teach that the hapten Proteus-DOTA permits efficient radiotherapy of solid tumor with alpha particle-emitting isotopes (such as 225Ac and 68Ga), and binds scFv C825 with high affinity. Proteus-DOTA has the structure:
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3-arm DOTA chelating Boxed portion: non-radioactive Benzyl-DOTA-Lu
agent (loads 225Ac or 68Ga) recognized by scFv C825
Thus, Proteus-DOTA is identical to the elected hapten and is a species encompassed Formula II recited in claim 51. See [0026]; [0042]-[0043]; [0073]-[0075]; [0112]-[0114]; [0118]; [0120]; [0130]; [0141]; Fig. 1 and 5.
Based on these teachings in Cheal et al., one of skill in the art would have found obvious to further replace 86Y-AABD with Proteus-DOTA and the CD19 scFv with an scFv targeting a solid tumor antigen, to achieve the predictable result of obtaining a composition suitable to treat solid tumors, when treating solid tumors was needed.
Cheal et al. do not specifically teach that the scFv C825 has the sequence set forth by SEQ ID NO: 37 (claim 1). Powell et al. teach the humanized scFv C825 having the amino acid sequence set forth by SEQ ID NO: 2, which is identical to the claimed SEQ ID NO: 37 (see p. 39, Table 1; see the attached Sequence Alignment). Using the scFv C825 taught by Powell et al. would have been obvious to one of skill in the art to achieve the predictable result of obtaining genetically engineered T-cells expressing on their surface a reporter enabling tracking in vivo.
With respect to claims 29, 30, 33, 34, 42, 43, and 47, Krebs et al. teach transducing the T-cells with two retroviral and not with a single retroviral vector. However, Krebs et al. teach that multiple genes can be expressed from the same vector and from the same promoter if they are separated by a P2A sequence (see p. 1895, column 1, second paragraph and Fig. 1). Thus, subcloning the CAR and anti-DOTA scFv C825 together with a sequence encoding a P2A self-cleaving peptide into a single retroviral vector would have been obvious to one of skill in the art, to achieve the predictable result of obtaining engineered T-cells suitable to be used for treating solid tumors. By doing so, one of skill in the art would have used a retroviral vector as recited in claims 42, 43, and 47 and would have obtained a polypeptide as recited in claims 29, 30, 33, and 34.
With respect to claim 6, in order to be expressed by the genetically engineered T-cell, the retroviral vector must necessarily contain a promoter operably linked to the nucleic acid encoding the anti-DOTA scFv C825.
With respect to claims 55 and 57, Krebs et al. teach detecting accumulation within tumors by (i) administering the engineered T-cells; (ii) intravenously administering radiolabled DOTA to tag the engineered T-cells via binding the anti-DOTA scFv; and (iii) using PET to detect the accumulation of the tagged engineered T-cells within tumors. Furthermore, Cheal et al. teach detecting tumors by: (i) administering scFv C825 and radiolabeled Proteus-DOTA as a preformed complex; and (ii) using PET to detect the radioactive levels emitted by the complex, where radioactive levels higher than the control indicate the presence of tumors (see [0085]-[0087]).
Thus, administering the genetically engineered T-cells and radiolabeled Proteus-DOTA to a subject either sequentially or as a precomplex would have been obvious to one of skill in the art, with the reasonable expectation that doing so would detect whether the subject has cancer. By doing so, one of skill in the art would have also monitored the biodistribution of the genetically engineered T-cells (claims 65 and 71).
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
10. Claims 1, 6, 13, 15, 16, 24, 29, 30, 33, 34, 42, 43, 47, 51, 55, 57, 65, 67, 70, and 71 are rejected under 35 U.S.C. 103 as being unpatentable over Krebs et al. taken with both Cheal et al. and Powell et al., in further view of Krebs et al. (J. Nucl. Med., online May 3, 2019, 60: 879-881; Krebs1).
The teachings of Krebs et al., Cheal et al., and Powell et al. are applied as above for claims 1, 6, 13, 15, 16, 24, 29, 30, 33, 34, 42, 43, 47, 51, 55, 57, 65, and 71. Krebs et al., Cheal et al., and Powell et al. do not specifically teach monitoring the viability and proliferation of the genetically engineered T-cells (claims 67 and 70). Krebs1 teach that, as the reporter gene is passed on to the cell progeny, the binding of anti-DOTA scFv to DOTA could be used to monitor the proliferation of the transplanted T-cells via PET, where measuring proliferation also provides information about viability (see p. 879, column 2, first paragraph; p. 880, column 1, second and third paragraphs). Thus, determining the radioactivity levels at first and second points as compared to the control would have been obvious to one of skill in the art, with the reasonable expectation that doing so would allow monitoring the viability of the transplanted T-cells. Furthermore, administering Proteus-DOTA before the second point would have been obvious to one of skill in the art to achieve the predictable result of determining the number of progeny cells, and thus, monitoring the expansion of the genetically engineered cells after transplantation in the subject.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
11. No claim is allowed. No claim is free of prior art.
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/ILEANA POPA/Primary Examiner, Art Unit 1633