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 .
Priority
The instant application, filed on 24 August, 2023 claims domestic benefit to US provisional application no. 63/400,740, filed on 24 August, 2022.
Status of Application, Amendments, and/or Claims
The response filed on 24 August, 2023 has been entered in full. No amendments or withdrawals have been made. Therefore, claims 1-20 are pending and are the subject of this Office Action.
Claim Objections
Claims 8 and 9 are objected to because of the following informalities: both claims recite “said macrophages are CD14+ cells comprise a population of.” This statement is grammatically incorrect. Appropriate correction is required.
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.
Claims 4, 5, 6, 7, and 11-17 are rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention.
Claim 5 recites the limitation "wherein the intracellular signaling domain". There is insufficient antecedent basis for this limitation in the claim. Further, claim 3 from which it depends does not recite claim to an intracellular signaling domain, however claim 4 does. For the purpose of further examination claim 5 will be interpreted to be dependent on claim 4.
Claim 6 recites the limitation "wherein the intracellular signaling domain". There is insufficient antecedent basis for this limitation in the claim. Further, claim 3 from which it depends does not recite claim to an intracellular signaling domain, however claim 4 does. For the purpose of further examination claim 6 will be interpreted to be dependent on claim 4.
Claim 7 recites the limitation "wherein the transmembrane domain". There is insufficient antecedent basis for this limitation in the claim. Further, claim 3 from which it depends does not recite claim to a transmembrane domain, however claim 4 does. For the purpose of further examination claim 7 will be interpreted to be dependent on claim 4.
Claim 12 recites the limitation "wherein the recombinant polynucleic acid". There is insufficient antecedent basis for this limitation in the claim. Further, claim 3 from which it depends does not recite claim to a recombinant polynucleic acid, however claim 11 does. For the purpose of further examination claim 12 will be interpreted to be dependent on claim 11.
Claim 14 recites the limitation "wherein the intracellular domain". There is insufficient antecedent basis for this limitation in the claim. Further, claim 3 from which it depends does not recite claim to an intracellular domain, however claim 4 does. For the purpose of further examination claim 14 will be interpreted to be dependent on claim 4.
Claims 4, 11, and 13-17 recites the limitation “the human subject”. There is insufficient antecedent basis for this limitation in the claims. Further, claim 3 from which they depend does not recite claim to a human subject. For the purpose of further examination and in light of the specification which states “the patient, subject or individual is a human” (paragraph 00233) the claims will be interpreted to mean a human subject.
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 1-3, 8, and 18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Klichinsky et al. (2020) Human chimeric antigen receptor macrophages for cancer immunotherapy Nature Biotechnology (38) 947-953 (hereafter Klichinsky) as evidenced by Boyette et al. (2017) Phenotype, function, and differentiation potential of human monocyte subsets PLoS ONE 12(4): e0176460 (hereafter Boyette).
In regards to claims 1,2, and 3 Klichinsky anticipates the development and use of an immune cell modified with a chimeric antigen receptor (CAR) for the treatment of cancer and further wherein said immune cells are macrophages (CD14 expressing cells) (pg.947, col 2, lines 21-26).
In regards to claim 8 Klichinsky anticipates the use of monocyte derived macrophages using GM-CSF as the differentiating agent (pg.954 (methods), col 2, lines 32-35) which produces CD14+/CD16+ macrophages as evidenced by Boyette. Boyette teaches that differentiation of monocytes with GM-CSF gives rise to M1 macrophages (pg.4, lines 28-30) which express both CD14+ and CD16+ (Figure 6E). Thus, the methods used by Klichinsky anticipate a population of macrophages which are CD14+ and CD16+.
In regards to claim 18 Klichinsky anticipates that CAR-Ms have increased phagocytic activity (Figure 1).
Claim Rejections - 35 USC § 103
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.
Claims 4-7, 10-17 are rejected under 35 U.S.C. 103 as being unpatentable over Klichinsky in view of Gill and Klichinsky (WO2019152781) as evidenced by Boyette.
Klichinsky teaches the development and use of an immune cell modified with a chimeric antigen receptor (CAR) for the treatment of cancer and further wherein said immune cells are macrophages (CD14 expressing cells) as applied above to in the 102 rejection of claims 1-3.
Klichinsky also teaches In regards to claim 4 the CAR having an extracellular domain comprising an antigen binding domain, a transmembrane domain, and an intercellular domain containing an intracellular signaling domain and a pharmaceutically acceptable carrier (PBS) (Supplementary Figure 1/ pg.954 (methods), col 1, lines 38-39).
In regards to claim 5 Klichinsky teaches that the intracellular signaling domains can CD3 zeta or FcR gamma (pg.947, col 2, lines 21-26).
In regards to claim 7 Klichinsky teaches that the transmembrane domain can be CD8a (Supplemental Figure 1a and 1g).
In regards to claim 11 Klichinsky teaches the transfecting of isolated primary human monocyte cells with a nucleic acid sequence encoding the CAR (pg.954 (methods), col 2, lines 23-43) and further administering the cells to a human tumor model in an immunodeficient mouse by intravenous injection (infusion) (pg. 954 (methods), col 1, lines 38-40).
In regards to claims 13 and 15 Klichinsky teaches that the CAR-Ms mediate potentiation of nonspecific T cell anti-tumor activity (effector function) (pg.952, col 1, lines 4-6).
In regards to claim 16 Klichinsky teaches that the CAR-Ms decrease tumor burden significantly compared to untreated or empty vector treated macrophages (Figure 2).
In regards to claim 17 Klichinsky teaches the CAR-Ms are capable of exerting dominant effects on surrounding immune cells and maintain their anti-tumor activity in the presence of M2 macrophages (pro tumoral, pg.947, col 1, lines 1-3) (pg.951, col 2, lines 2-5 and Figure 3j).
Klichinsky fails to teach the options of intracellular signaling domains Fc.epsilon.R or TRIF of claim 5, the option of a TLR4 transmembrane domain of claim 7, and the two or more intracellular domains of claim 6. Klichinsky also fails to teach the CD14+ dendritic or CD14+ monocyte populations of claim 10. Klichinsky further fails to teach the treatment of human subjects of claims 4 and 11-17, the recombinant polynucleic acid where it is mRNA of claim 12, and the CAR capable of monocytic differentiation of claim 14.
Gill and Klichinsky however, in regards to claim 5 teaches that the intracellular domain can be selected from a list of co-stimulatory molecules including FcR gamma, CD3 zeta, and Fc Epsilon R1b to dampen or heighten initial stimulus (Claim 14 of Gill and Klichinsky and pg.17 lines 10-11).
In regards to claim 6 Gill and Klichinsky teach the CAR comprising more than one intercellular signaling domain (Claim 13 of Gill and Klichinsky).
In regards to claim 7 Gill and Klichinsky teach the transmembrane domain can come from a list of proteins which include CD8 and TLR4 (pg. 43, lines 13-19).
In regards to claims 4 and 11-17 Gill and Klichinsky teach the applicability of these CAR immune cells for use in the treatment of human subject as highly preferable (pg.66 lines 10-11). It is also noted that Klichinsky uses a humanized mouse model highlighting transferability to a human model (abstract).
In regards to claim 10 Gill and Klichinsky teach the use of monocytes and dendritic cells as options for CAR transduction, both of which are capable of expressing CD14+ as evidenced by Boyette. Boyette teaches that CD14+ is expressed on monocytes (pg.2, lines 22-24 and 31-32) and further teach that dendritic cells are derived from differentiation of monocytes and that specifically intermediate monocytes differentiate into dendritic like cells still express CD14+ (pg.7, lines 30-31). Thus, Gill and Klichinsky’s teachings of the use of monocytes and dendritic cells teach a CD14+ monocyte or CD14+ dendritic cell.
In regards to claim 12 Gill and Klichinsky teach introducing the CAR into the cell using a mRNA as a method to develop the therapeutic (pg.53 lines 15-18).
In regards to claim 14 Gill and Klichinsky teach the attachment of Co-stimulatory ligands to the intracellular domain which bind to cognate co-stimulatory molecule on monocytes to provide a signal which can mediate differentiation (pg. 16 lines 30-34).
Thus, Klichinsky discloses a CAR-M which has an intracellular domain of CD3 zeta or FcR gamma and a transmembrane domain of CD8a for the treatment of cancer which can modulate T cell effector function, inhibit tumor growth, kill cancer cells, and improve phagocytosis. Gill and Klichinsky teach a CAR which can be in monocytes , macrophages, or dendritic cells which can contain one or more intracellular domains which can comprise CD3 zeta, FcR gamma, or FcR epsilon, and further has a transmembrane domain of either CD8 or TLR4. Gill and Klichinsky also teach the attachment of a Co-stimulatory ligand to mediate differentiation of monocytes with a CAR and suggest that treatment use in human is highly desirable. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings of Klichinsky with the teachings and suggestions of Gill and Klichinsky with a reasonable expectation of success to develop the CAR immune cell options of the claims to treat cancer in human subjects by mediating T cell effector function, increasing phagocytosis, or directly killing cancer cells.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Klichinsky in view of Acker et al. (2017) CD56 in the Immune System: More Than a Marker for Cytotoxicity? Front. Immunol (8) 892 (hereafter Acker) and Boyette.
Klichinsky teaches a macrophage modified by a CAR for the treatment of cancer as outlined above in the 102 rejection of claim 2. Klichinsky fails to teach the CD14+/CD56+ macrophage population, however Acker teaches CD14+/CD56+ cells are a variation of monocyte (innate immune cell) which are able to infiltrate into tumor lesions and have direct cytolytic activity toward malignant cells upon activation (pg. 5, col 2, lines 27-31).
Thus, Klichinsky discloses a macrophage modified by a CAR for the treatment of cancer, and Acker teaches that a CD14+/CD56+ cell monocyte phenotype is able to infiltrate into tumor lesions and have cytolytic activity towards malignant cells. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to use the teachings of Klichinsky informed by the teachings of Acker to select the CD14+/CD56+ cell population with a reasonable expectation of success to develop a CAR-Macrophage with increased ability to infiltrate and kill cancer.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Klichinsky in view of
Hume and MacDonald (2012) Therapeutic applications of macrophage colony stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling Blood (119) 8, 1810-1820 (hereafter Hume and MacDonald).
Klichinsky teaches the CAR modified macrophage for the treatment of cancer as outlined above in 102 rejection of claim 3. Klichinsky fails to teach the administration of M-CSF as part of the treatment. Hume and MacDonald, however, teaches that administration of CSF-1 (M-CSF) to humans receiving bone marrow transplantation or recovering from myelosuppressive chemotherapy resulted in reduced circulating granulocyte recovery time and improved survival without retransplantation (pg.1813, col 1, lines 1-8). Further, Hume and MacDonald teach the infusion of recombinant CSF-1 in humans with advanced melanoma increased circulating monocytes. (pg.1813, col 1, lines 20-23).
Thus, Klichinsky discloses a CAR modified macrophage for the treatment of cancer, and Hume and MacDonald teach administration of CSF-1 in humans reduced circulating granulocyte recovery time and increased circulating monocytes. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings of Klichinsky with the teachings of Hume and MacDonald with a reasonable expectation of success to develop a CAR-M to treat cancer in which the subject is also administered M-CSF to increase the efficacy of the treatment by stimulating circulating monocytes and reduce circulating granulocyte recovery time to improve survival.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Klichinsky in view of Fishelson and Kirschfink (2019) Complement C5b-9 and Caner: Mechanisms of Cell Damage, Cancer Counteractions, and Approaches for Intervention Front. Immunol. (10)752 (hereafter Fishelson and Kirschfink).
Klichinsky teaches the CAR modified macrophage for the treatment of cancer as outlined above in the 102 rejection of claim 3. Klichinsky fails to teach the administration of C5 component of complement as part of the treatment. Fishelson and Kirschfink, however, teaches that C5 is cleaved in the body to develop membrane attack complexes (MAC) (pg.2, col 1, lines 8-10) which can have anti-cancer cytotoxicity (pg.2, col 1, lines 11-13) dependent upon the rate and extent of formation and insertion of MAC into the target cell membrane (pg.5, col 2, lines 2-4). Further Fishelson and Kirschfink teach a method of using anti-cancer antibodies to enhance anti-tumor activity and increase sensitivity to complement (Figure 2/ pg.9 col 1, lines 5-30).
Thus, Klichinsky discloses a CAR modified macrophage for the treatment of cancer, and Fishelson and Kirschfink teaches the benefits of increased C5 of component with an anti-cancer antibody to increase cytotoxicity to cancer cells. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings of Klichinsky with the teachings of Fishelson and Kirschfink with a reasonable expectation of success to develop a CAR-M to treat cancer in which the subject is administered C5 component of complement to increase the amount of MAC available to the cell to increase cancer cell death.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DASIA A ALDARONDO whose telephone number is (571)272-1977. The examiner can normally be reached on Monday – Thursday from 7am to 4pm and Friday 7am to 11am.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at telephone number (571)272-2911. The fax phone number for the organization where this application or proceeding is assigned is (571)273-8300.
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/D.A.A/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647