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 .
Claims 1-8, 17, 21, 23-25, 27, 29-31, 35, 83 and 85 are pending in the present application.
Applicant’s election without traverse of the following species in the reply filed on 09/29/2025 is acknowledged.
Applicant elected: (i) administering to the subject a plurality of recombinant retroviral particles; (ii) the viral envelope comprises one or more transduction enhancers; (iii) T-cell activation activator as a species of one or more transduction enhancers; (iv) anti-CD3scFv as a species of T-cell activation activator; (v) folate as a species of a targeting moiety; and (vi) rapamycin as a species of a molecule to induce binding of first and second dimerization domains.
Accordingly, claims 2, 4-6, 21, 23-24 and 83 are withdrawn from further considerations because they are directed to non-elected species.
Therefore, claims 1, 3, 7-8, 17, 25, 27, 29-31, 35 and 85 are examined on the merits herein with the above elected species.
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.
Claims 1, 3, 7-8, 17, 25, 27, 29-31, 35 and 85 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.
The term “specifically binds” in claims 1 and 29-31 is a relative term which renders the claim indefinite. The term “specifically binds” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. For example, which binding and/or at which minimal binding affinity that a binding would or would not be considered to be “specifically binds”. Clarification is requested because the metes and bounds of the claims are not clearly determined.
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, 17 and 31 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Low et al (WO 2017/177149).
The instant claims are directed to a method, comprising: (a) administering to a subject an adaptor molecule comprising a targeting moiety (e.g., folate) and a hapten; and (b) administering to the subject either (i) a plurality of recombinant retroviral particles (e.g., lentiviral particles) or (ii) immune cells that have been contacted ex vivo with a plurality of recombinant retroviral particles, wherein each of the retroviral particles comprises a polynucleotide comprising a sequence encoding a receptor that specifically binds to the hapten; and wherein each of the retroviral particles comprises a viral envelope.
Low et al already disclosed a method of treating a patient with a cancer by administering to the patient a composition comprising CAR T cells and administering to the patient a small molecule ligand (folate, DUPA, an NK-1R ligand and others, each of which is a small molecule ligand that binds specifically to cancer cells overexpressing the receptor for each of these ligands relative to normal tissues) linked to a targeting moiety (e.g., 2,4-dinitrophenol (DNPP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC) and others) by a linker, wherein the recognition region of the CAR (e.g., single chain fragment variable region (scFv) of an antibody) is directed to the targeted moiety and the linker acts as a “bridge” between the cancer and the CAR T cells directing the CAR T cells to the cancer for amelioration of the cancer (Abstract; and Summary of the Invention; particularly line 18 at page 2 continues to line 5 at page 3; pages 25-26; and Example 6). Low et al also taught constructs encoding the CARs are prepared using genetic engineering techniques, and a viral expression vector such as a lentiviral vector or a retrovirus vector can be prepared that encodes a fusion protein comprising a recognition region, one or more co-stimulation domains, and an activation signaling domain, in frame and in a 5’ to 3’ direction. An exemplary CAR construct encoding a fusion protein is incorporated into a lentivirus expression vector is shown in Fig. 14A-B below. Example 2 shows the production and harvest of lentivirus particles containing the CAR gene, while Example 4 demonstrated the transduction of human T cells with lentivirus encoding the anti-fluorescein CAR gene.
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Low et al also taught that at least a population of autologous cytotoxic T lymphocytes was obtained, cultured in vitro under conditions that promote the activation of the cells, and transfecting the lymphocytes with an expression vector encoding a CAR to form CAR T cells (pages 36-37). Low et al further taught that the small molecule ligand linked to the targeting moiety can be administered to the patient before, at the same time, or after the CAR T cell composition (page 42, lines 1-6).
Accordingly, the teachings of Low et al meet every limitation of an embodiment (immune cells that have been contacted ex vivo with a plurality of recombinant retroviral particles) of the instant claims. Therefore, the reference anticipates the instant claims.
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 1, 3, 7-8, 17, 25, 31, 35 and 85 are rejected under 35 U.S.C. 103 as being unpatentable over Low et al (WO 2017/177149) in view of Pule et al (WO 2016/139463; IDS) and Jensen et al (WO 2019/156795; IDS).
With respect to the elected species, Low et al already disclosed a method of treating a patient with a cancer by administering to the patient a composition comprising CAR T cells and administering to the patient a small molecule ligand (folate, DUPA, an NK-1R ligand and others, each of which is a small molecule ligand that binds specifically to cancer cells overexpressing the receptor for each of these ligands relative to normal tissues) linked to a targeting moiety (e.g., 2,4-dinitrophenol (DNPP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC) and others) by a linker, wherein the recognition region of the CAR (e.g., single chain fragment variable region (scFv) of an antibody) is directed to the targeted moiety and the linker acts as a “bridge” between the cancer and the CAR T cells directing the CAR T cells to the cancer for amelioration of the cancer (Abstract; and Summary of the Invention; particularly line 18 at page 2 continues to line 5 at page 3; pages 25-26; and Example 6). Low et al also taught constructs encoding the CARs are prepared using genetic engineering techniques, and a viral expression vector such as a lentiviral vector or a retrovirus vector can be prepared that encodes a fusion protein comprising a recognition region, one or more co-stimulation domains, and an activation signaling domain, in frame and in a 5’ to 3’ direction. An exemplary CAR construct encoding a fusion protein is incorporated into a lentivirus expression vector is shown in Fig. 14A-B below. Example 2 shows the production and harvest of lentivirus particles containing the CAR gene, while Example 4 demonstrated the transduction of human T cells with lentivirus encoding the anti-fluorescein CAR gene.
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Low et al also taught that at least a population of autologous cytotoxic T lymphocytes was obtained, cultured in vitro under conditions that promote the activation of the cells, and transfecting the lymphocytes with an expression vector encoding a CAR to form CAR T cells (pages 36-37). Low et al further taught that the small molecule ligand linked to the targeting moiety can be administered to the patient before, at the same time, or after the CAR T cell composition (page 42, lines 1-6).
Low et al did not teach a method of treating a patient with a cancer by administering to the patient a composition comprising a plurality of recombinant retroviral particles (elected species) and administering to the patient a small molecule ligand (e.g., folate, DUPA, an NK-1R ligand and others, each of which is a small molecule ligand that binds specifically to cancer cells overexpressing the receptor for each of these ligands relative to normal tissues) linked to a targeting moiety (e.g., biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC)) by a linker, wherein each of the retroviral particles comprises a polynucleotide comprising a sequence encoding a receptor that specifically binds to the targeting moiety/hapten to transduce T cells in the subject; and wherein the each of the retroviral particles comprises a viral envelope comprising one or more transduction enhancers (e.g., T-cell activation receptor such as anti-CD3scFv; elected species, claims 7-8 and 25); and/or using a masked targeting moiety/hapten to label cancer cells (claim 85).
Before the effective filing date of the present application (10/16/2019), Pule et al already disclosed at least a retroviral or lentiviral vector having a viral envelope which comprises a mitogenic T-cell activating transmembrane domain comprising a mitogenic domain and a transmembrane, wherein the mitogenic T-cell activating transmembrane protein is not part of a viral envelope glycoprotein as depicted in Fig. 1 below, and that the vector may be used to transduce and activate cells such as T-cells as well as to effect gene insertion (Abstract; Summary of aspects of the Invention; particularly page 9, lines 9-29; pages 15-22; and Example 1).
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Pule et al stated “The invention involves including a mitogenic transmembrane protein and/or a cytokine-based transmembrane domain in the producer or packaging cell, which get(s) incorporated into the retrovirus when it buds from the producer/packaging cell membrane. The mitogenic transmembrane protein and/or a cytokine-based transmembrane protein is/are expressed as a separate surface molecule on the producer cell rather than being part of the viral envelope glycoprotein. This means that the reading frame of the viral envelope is unaffected, which therefore preserves functional integrity and viral titre” (page 4, first paragraph). Pule et al disclosed that the mitogenic T-cell activating transmembrane protein may bind an activating T-cell surface antigen such as CD3, CD28, CD134 or CD137; and that the mitogenic T-cell activating transmembrane protein may comprise the binding domain from an antibody such as OKT3, 15E8, TGN1412, including the exemplary OKT3scFv attached to the membrane via a CD8 stalk or via an IgG1 hinge’s ability to incorporate into a lentivirus (Example 1). Pule et al also taught that the viral vector may comprise a heterologous viral envelope glycoprotein giving a pseudotyped viral vector, and that the viral envelope glycoprotein may be derived from RD114, VSV-G, Gibbon-ape leukaemia virus (GALV), Measles envelope or baboon retroviral envelope glycoprotein (page 6, second paragraph). Pule et al also disclosed that the viral vector may be used as a vector or delivery system for the transfer of a nucleotide of interest (NOI), or a plurality of NOIs, to a target cell, and such transfer can occur in vitro, ex vivo or in vivo; and that the NOI may encode a T cell receptor or a chimeric antigen receptor and/or a suicide gene (page 11, lines 14-20).
Additionally, Jensen et al also taught a method of treating or ameliorating a cancer in a subject comprising: a) introducing or administering to the subject a composition that comprises a lipid (e.g., phospholipid ether (PLE)), which comprises a target moiety (e.g., biotin, digoxigenin, dinitrophenol or fluorescein) that is bound to a masking moiety; b) introducing or administering to said subject a T cell comprising a chimeric antigen receptor (CAR) or T cell receptor (TCR), which is specific for the target moiety once the masking moiety is removed from the target moiety, and wherein the CAR or TCR comprises a spacer domain; and c) removing the masking moiety from the target moiety, thereby allowing the target moiety to bind to the CAR present on the cell; and wherein the masking moiety is unmasked in the presence of low pH, ROS species and within a tumor microenvironment (Abstract; Summary; particularly paragraphs [0005]-[0007], [0009]-[0012], [0052]; and Figs. 1-4).
Accordingly, it would have been obvious to one of ordinary skill in the art to modify the method of treating a patient with a cancer of Low et al by also administering to the patient a plurality of recombinant retroviral particles, wherein each of the retroviral particles comprises a polynucleotide comprising a sequence encoding a receptor such as a CAR that specifically binds to the targeting moiety/hapten such as DNPP, biotin, digoxigenin, fluorescein, or fluorescein isothiocyanate (FITC), including recombinant retroviral particles wherein each of the retroviral particles comprises a viral envelope comprising one or more transduction enhancers (e.g., T-cell activation receptor such as anti-CD3scFv) to transduce and activate at least endogenous T cells in the subject, particular recruited endogenous T cells to a tumor; and/or further activate administered CAR T cells; as well as using a masked hapten such as a masked biotin, digoxigenin, dinitrophenol or fluorescein to label cancer cells in the subject; in light of the teachings of Pule et al and Jensen et al as set forth above.
An ordinary skilled in the art would have been motivated to carry out the above modifications because: (i) Pule et al already disclosed at least a retroviral or lentiviral vector having a viral envelope which comprises a mitogenic T-cell activating transmembrane domain comprising a mitogenic domain and a transmembrane, wherein the mitogenic T-cell activating transmembrane protein is not part of a viral envelope glycoprotein, and that the viral vector may be used to transduce and activate cells such as T-cells in vitro, ex vivo or in vivo as well as to effect gene insertion; and the viral vector may comprise one or more NOIs that include a NOI that encodes a CAR; and (ii) Jensen et al also taught a method of treating or ameliorating a cancer in a subject using a composition that comprises a lipid which comprises a target moiety (e.g., biotin, digoxigenin, dinitrophenol or fluorescein, all of which is a hapten in the context of the present application) that is bound to a masking moiety, wherein the masking moiety is unmasked in the presence of low pH, ROS species and within a tumor microenvironment to allow the target moiety to bind to the CAR present on a T-cell (a means to control activation of CAR-T cells at a tumor site or in a tumor microenvironment to limit off-target adverse side effects).
An ordinary skilled artisan would have a reasonable expectation of success to carry out the above modifications in light of the combined teachings of Low et al, Pule et al and Jensen et al as set for the above; coupled with the level of skill for an ordinary skilled artisan in the relevant art.
The modified method resulting from the combined teachings of Low et al, Pule et al and Jensen et al as set forth above is indistinguishable and encompassed by the presently claimed invention.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claims 27 and 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over Low et al (WO 2017/177149) in view of Pule et al (WO 2016/139463; IDS) and Jensen et al (WO 2019/156795; IDS) as applied to claims 1, 3, 7-8, 17, 25, 31, 35 and 85 above, and further in view of Scharenberg (WO 2018/111834; IDS).
The combined teachings of Low et al, Pule et al and Jensen et al were presented above. However, none the cited references teach or suggest that each of the retroviral particles comprises a polynucleotide comprising a sequence encoding at least one T-cell activator protein which comprises a first receptor protein comprising a first dimerization domain and a second receptor protein comprising a second dimerization domain, and wherein the first dimerization domain and the second dimerization domain specifically bind to one another in response to a molecule such as a rapamycin (elected species).
Before the effective filing date of the present application (10/16/2019), Scharenberg already disclosed methods of exogenous drug activation of chemical-induced signaling complexes expressed in engineered T cells in vitro and in vivo for selective expansion of cells (Abstract and Summary). Scharenberg taught a chemical-induced signaling complex (CISC) comprising: (i) a first CISC component comprising a first extracellular binding domain (e.g., an FKBP domain), a hinge domain, a transmembrane domain, and a signaling domain, and (ii) a second CISC component comprising a second extracellular binding domain (e.g., an FRB domain), a hinge domain, a transmembrane domain, and a signaling domain; wherein the first CISC component and the second CISC component are positioned such that when expressed, they dimerize in the presence of a ligand (e.g., rapamycin or a rapalog such as everolimus, CCI-779, C20-methallyrapamycin, AP23573, AP1903); and expression vectors (e.g., a lentiviral vector or an AAV vector) comprising a nucleic acid encoding the above CISC (paragraphs [0006]-[0010], [0013], [0015], and [0017]-[0018]). Scharenberg stated “In some embodiments, the ligand comprises rapamycin and the cells, such as a mammalian cell, expressing the chemical-induced signaling complex are selectively expanded in vitro or in vivo by selectively inducing proliferation in chemical-induced signaling complex-expressing cells, while rapamycin, preferably simultaneously, causes an anti-proliferative effect in non-chemical-induced signaling complex expressing cells, such as mammalian cells” (the sentence bridging pages 8-9).
Accordingly, it would have been obvious to one of ordinary skill in the art to further modify the combined teachings of Low et al, Pule et al and Jensen et al by also further incorporate a sequence encoding a chemical-induced signaling complex (CISC) in a polynucleotide containing in each of recombinant retroviral particles, in light of the teachings of Scharenberg as set forth above.
An ordinary skilled in the art would have been motivated to further carry out the above modification because Scharenberg already taught exogenous drug activation of chemical-induced signaling complexes expressed in engineered T cells in vitro and in vivo for selective expansion of cells that is useful and beneficial for cancer treatment.
An ordinary skilled artisan would have a reasonable expectation of success to further carry out the above modification in light of the combined teachings of Low et al, Pule et al, Jensen et al and Scharenberg as set for the above; coupled with the level of skill for an ordinary skilled artisan in the relevant art.
The modified method resulting from the combined teachings of Low et al, Pule et al, Jensen et al and Scharenberg as set forth above is indistinguishable and encompassed by the presently claimed invention.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Quang Nguyen, Ph.D., whose telephone number is (571) 272-0776.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s SPE, James Douglas (Doug) Schultz, Ph.D., may be reached at (571) 272-0763.
To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Group Art Unit 1631; Central Fax No. (571) 273-8300.
Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to (571) 272-0547.
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/QUANG NGUYEN/Primary Examiner, Art Unit 1631