SEQ 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 .
Applicant’s amendment filed on 03/31/2026 has been entered.
Amended claims 1, 3-8, 17, 21, 23-25, 27, 29-31, 35, 83, 85 and new claim 90 are pending in the present application.
Applicant elected previously without traverse the following species: (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.
Claims 4-6, 21, 23-24 and 83 are withdrawn from further considerations because they are directed to non-elected species.
Accordingly, amended claims 1, 3, 7-8, 17, 25, 27, 29-31, 35, 85 and 90 are examined on the merits herein with the above elected species.
Response to Amendment
The rejection under 35 U.S.C. 102(a)(1) as being anticipated by Low et al (WO 2017/177149) was withdrawn in light of currently amended independent claim 1, particularly with the deletion of the limitation “immune cells that have been contacted ex vivo with a plurality of recombinant retroviral particles”.
Claim Rejections - 35 USC § 112 (Scope of Enablement)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Amended claims 1, 3, 7-8, 17, 25, 27, 29-31, 35 and 90 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
A method of treating cancer or killing cancer cells in a subject, the method comprising:
(a) administering to a subject an adaptor molecule comprising a targeting moiety and a hapten; and
(b) administering to the subject a plurality of recombinant retroviral particles,
wherein each of the retroviral particles comprises a polynucleotide comprising a sequence encoding a receptor that binds to the hapten; and
wherein each of the retroviral particles comprises a viral envelope;
does not reasonably provide enablement for a method for treating other disease or disorder in a subject as claimed broadly. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims. This is a new ground of rejection necessitated by Applicant’s amendment.
The factors to be considered in the determination of an enabling disclosure have been summarized as the quantity of experimentation necessary, the amount of direction or guidance presented, the state of the prior art, the relative skill of those in the art, the predictability or unpredictability of the art and the breadth of the claims. Ex parte Forman, (230 USPQ 546 (Bd Pat. Appl & Unt, 1986); In re Wands, 858 F.2d 731, 8 USPQ 2d 1400 (Fed. Cir. 1988)).
The instant specification is not enabled for the instant broadly claimed invention for the reasons discussed below.
1. The breadth of the claims
The instant claims encompass a method for treating any disease or disorder (e.g., cancers or tumors; neurodegenerative diseases/disorders such as ALS, Alzheimer’s disease, Parkinson’s disease; complex autoimmune conditions such as lupus, scleroderma, multiple sclerosis; rare and genetic diseases such as Idiopathic Pulmonary Fibrosis and Fibrodysplasia Ossificans Progressia; and ocular diseases such as retinitis pigmentosa, glaucoma, Acanthamoeba keratitis) in a subject, the method comprising: (a) administering to a subject an adaptor molecule comprising a targeting moiety (e.g., a folate or a phosphor-lipid-ether) and a hapten (e.g., 2,4-dinitrophenol (DNPP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC)); and (b) administering to the subject a plurality of recombinant retroviral particles, wherein each of the retroviral particles comprises a polynucleotide comprising a sequence encoding a receptor that binds to the hapten; and wherein each of the retroviral particles comprises a viral envelope.
2. The state and the unpredictability of the prior art
Before the effective filing date of the present application (10/16/2019), little was known about a method of treating any disease or disorder in a subject comprising the steps (a)-(b) as claimed broadly in independent claim 1 as evidenced at least by the teachings of Low et al (WO 2017/177149), Pule et al (WO 2016/139463; IDS), Jensen et al (WO 2019/156795; IDS), Scharenberg (WO 2018/111834; IDS), Pfeiffer article (EMBO Mol Med 10:e9158, doi:10.15252/emmm.201809158, 2018), Zhou et al (Blood 120:4334-4342, 2012) and Zhou et al (J. Immunol. 195:2493-2501, 2015). The physiological art is already recognized as unpredictable (MPEP 2164.03), let alone an in vivo gene therapy for attaining a therapeutic effect for any disease or disorder in a subject as encompassed broadly by the instant claims.
3. The amount of direction or guidance provided
Apart from disclosing basically a method of treating a cancer or killing cancer cells in a subject using a retroviral vector for universal CAR T cell approach and without any in vivo example (see at least Abstract; Summary; and Example 1); the instant specification failed to provide sufficient guidance for an ordinary skilled artisan on how to make and use the combination of an adaptor molecule comprising a targeting moiety and a hapten, and recombinant retroviral particles comprising a sequence encoding a receptor that binds to the hapten to treat any disease or disorder in a subject other than cancers. For example, how transduced T cells resulting from the claimed method could provide any therapeutic effect for a subject in need of treatment for any neurodegenerative disease such as Alzheimer’s disease, Parkinson disease; any complex autoimmune condition such as lupus, scleroderma, multiple sclerosis; and/or any ocular disease such as retinitis pigmentosa, glaucoma, Acanthamoeba keratitis as encompassed broadly by the instant claims. What are the underlying working principles that yield therapeutic effects for these non-tumor diseases or disorders?
Since the prior art before the effective filing date of the present application failed to provide sufficient guidance regarding to the aforementioned issues, it is incumbent upon the present application to do so. Given the state of the prior art, coupled with the lack of sufficient guidance provided by the present application, it would have required undue experimentation for a skilled artisan to make and use the instant invention as claimed broadly.
As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112, first paragraph requires:
That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; in cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws; in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.
Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maizel.).
Accordingly, due to the lack of sufficient guidance provided by the specification regarding to the issues set forth above, the state and unpredictability of the relevant art, and the breadth of the instant claims, it would have required undue experimentation for one skilled in the art to make and use the instant broadly claimed invention.
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.
Amended claims 1, 3, 7-8, 17, 25, 31, 35, 85 and 90 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) for the same reasons already set forth in the Office Action dated 10/31/2025 (pages 5-11). The same rejection is restated below.
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, 85 and 90 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.
Response to Arguments
Applicant’s arguments related to the above 103 rejections in the Amendment filed on 03/31/2026 (pages 7-13) have been fully considered, but they are respectfully not found persuasive for the reasons discussed below.
A. Applicant argued basically that the Office has failed to identify how the cited combination of references teaches or suggests each and every element of the claimed treatment method, and the Office has provided no objective reasoning as to why the skilled artisan would have been motivated to perform the recited administration steps and why they would have any reasonable expectation of success of treating a disease or disorder using such administration steps.
(i) Specifically, Applicant argued that the Office has not identified any teaching in the combination of Low, Pule, and Jensen that suggest a method of treating a disease or disorder comprising the administration of the recited recombinant retroviral particles. Applicant argued that the Office’s rejection is reliant on the assertion that the passing mention of “in vivo” in the cited section of Pule amounts to a teaching of administering viral vectors to a subject for the treatment of a disease; but the disclosure of Pule is directed to the transduction of cultured cells either in an in vitro setting or an ex vivo setting, and each of the experimental examples provided by Pule are directed to in vitro and in vivo. (Pule at pages 31-35). Applicant also argued that Jensen fails to cure the deficiencies in the combination of Low and Pule because Jensen is directed solely to the ex vivo transduction and the administration of cellular therapies to a subject.
First, please note that since the above rejection was made under 35 U.S.C. 103 none of the cited references have to teach every limitation of the instant claims individually. It is also apparent that Applicant considered each of the cited references in total isolation one from the others, without taking into consideration of the specific combination of Low, Pule and Jensen as set forth in the above 103 rejection of record.
Second, Pule already disclosed the viral vector (e.g., 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, and that the vector may be used to transduce and activate cells such as T-cells as well as to effect gene insertion) 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). Thus, in the context of the combined teachings of Low, Pule and Jensen an ordinary skill in the art would readily recognize at least a method of treating a cancer in a patient 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 endogenous T cells to be recruited to a tumor; as well as using a masked hapten such as a masked biotin, digoxigenin, dinitrophenol or fluorescein to label cancer cells in the subject as set forth in the above 103 rejection of record. Thus, the combination of the cited references does teach each and every limitation of the instant claims along with motivation provided by Pule.
Third, the teachings of Pule are not necessarily limited to the transduction of cultured cells either in vitro or ex vivo, or in disclosed in vitro examples 1-5 in pages 31-35. Once again, Pule stated at least “Retroviruses and lentiviruses 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. The transfer can occur in vitro, ex vivo or in vivo. When used in this fashion, the viruses are typically called viral vectors” (page 11, lines 14-17). Similar to the Pule reference, it is interesting to note the as-filed specification of the present application also does not provide any in vivo example, let alone a method of treating any disease or any disorder in a subject as claimed broadly in currently amended independent claim 1.
Fourth, Jensen was cited to supplement the combined teachings of Low and Pule on the use of a target moiety (e.g., biotin, digoxigenin, dinitrophenol or fluorescein) 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.
Fifth, Scharenberg was cited to further supplement the combined teachings of Low, Pule and Jensen for the limitation recited in dependent claims 27 and 29-30.
(ii) Applicant argued that the unpredictable nature of in vivo cellular therapies renders the modification set forth in the Office action unpredictable and therefore non-obvious. Specifically, Applicant argued at the time of filing of the instant specification there existed numerous technical hurdles for in vivo cellular therapies by quoting “face a number of hurdles including efficiency, need for tissues restricted promoters, and immunogenicity” (Milone and O’Doherty, left column at page 1536; Exhibit A). Additionally, Applicant cited the Pfeiffer article (EMBO Mol Med 10:e9158, doi:10.15252/emmm.201809158, Published on line 17 September 2018; Exhibit B) demonstrating ever for any in vivo generation of human CAR T cells was made; and even then the initial in vivo CAR T cell therapy exhibited complications including substantially increased cytokines to the point of resembling cytokine release syndrome (Pfeiffer, left column of page 2); expressed concern that efficient and selective gene delivery into T cells in vivo represented a particular challenge, and that besides selectivity, the usual resting stated of T cells in vivo was not compatible with gene delivery by conventional lentiviral vectors. Applicant also cited the Zhang article (Biomark Res. 5:22. Doi: 10.1186/s40364-017-0102, 2017; Exhibit C) explaining that virus vectors such as retroviruses pose a potential safety hazard, and that “[t]he insertion mutation used to induce the immune reaction can lead to tumorigenesis and toxicity, the carrier capacity is limited and the titer achieved is not high enough” (Zhang, right column of page 3). Accordingly, given this unpredictability Applicant submits that the skilled artisan would not have modified the in vitro and ex vivo methods taught by Low, Pule and Jensen to the claimed in vivo method with any reasonable expectation of success.
First, Exhibit A simply stated generically “These approaches face a number of hurdles including efficiency, need for tissue-restricted promoters and immunogenicity. The latter is particularly important since immunogenicity can be related to both the delivered gene as well as components of the vector” (Milone &O’Doherty, right column, last full paragraph at page 1536). However, preceding immediately these statements Exhibit A also stated “Beyond the ex vivo modification of cells for adoptive transfer back into the patient, lentiviral vectors are also being applied directly in vivo for therapeutic purposes. A phase ½ study of a non-primate lentiviral vector based upon the equine infectious anemia virus (EIAV) expressing three genes involved in dopamine metabolism demonstrated the safety of local lentiviral delivery into the central nervous system with some evidence of clinical benefit [79]. In vivo gene delivery using a lentiviral vector has also been applied clinically to the eye [80]”. Thus, in the context of the combined teachings of Low, Pule and Jensen for treating cancer or killing cancer cells in a subject, the selected generic statements in Exhibit A that are quoted by Applicant do not indicate or suggest in any way that ordinary skilled artisan would not have a reasonable expectation of success to carry out the above modifications set forth in the above 103 rejection. Please note that the claims do not require any particular efficiency; any tissue-restricted promoter for expression of a receptor that binds to a hapten of an adaptor molecule in T cells in a subject; and that the standard under 35 U.S.C. 103 is a “reasonable” expectation of success.
Second, before the effective filing date of the present application (10/16/2019) the prior art in the form of the Pfeiffer article (EMBO Mol Med 10:e9158, doi:10.15252/emmm.201809158, Published on line 17 September 2018; Exhibit B) already stated clearly “Here, we provide evidence that human CD19-CAR T cells can be generated directly in vivo using the lentiviral vector CD8-LV specifically targeting human CD8+ cells. Administration into mice xenografted with Raji lymphoma cells and human peripheral blood mononuclear cells led to CAR expression solely in CD8+ T cells and efficacious elimination of CD19+ B cells. Further, upon injection of CD8-LV into mice transplanted with human CD34+ cells, induction of CAR T cells and CD19+ B-cell depletion was observed in 7 out of 10 treated animals. Notably, three mice showed elevated levels of human cytokines in plasma….Our data demonstrate the feasibility of in vivo reprogramming of human CD8+ CAR T cells active against CD19 cells, yet with similar adverse effects currently notorious in the clinical practice” (Abstract). Additionally, with respect to the combined teachings of Low, Pule and Jensen, Low already stated “[t]he inventors have discovered that varying the dose of the small molecule ligand linked to a targeting moiety by a linker (i.e., the bridge) can result in the ability to control CRS in vivo. In another embodiment, the inventors have discovered that varying the linker in the small molecule ligand linked to a targeting moiety (the bridge) can control CRS in vivo upon CAR T cell activation” (page 3, lines 6-10). Pule also 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 vector may be used to transduce and activate cells such as T-cells as well as to effect gene insertion. Moreover, before the effective filing date of the present application (10/16/2019), Zhou et al (Blood 120:4334-4342, 2012) already demonstrated successfully CD8-LV mediated stable in vitro and in vivo reporter gene transfer as well as efficient transfer of genes encoding TCRs recognizing the melanoma antigen tyrosinase to human CD8+ T cells to enhance tumor cell killing (see at least Abstract); while Zhou et al (J. Immunol. 195:2493-2501, 2015) also demonstrated the exclusive transfer into human CD4+ T cells upon systemic delivery of CD4-targeted lentiviral vectors (see at least Abstract). Accordingly, all these prior art support the Examiner’s position that an ordinary skilled artisan would have a reasonable expectation of success to carry out the modifications as set forth in the above 103 rejection in light of the combined teachings of Low, Pule and Jensen; coupled with the level of skill for an ordinary skilled artisan in the relevant art.
Third, with respect to the general review of Zhang et al (Exhibit C) although there are challenges or questions still need to be addressed such as the optimal vector and the long-term safety profile, the fact remains that CAR T-cells have been used in clinics (right column, first paragraph at page 4). Zhang et al also taught that it is necessary to monitor carefully any potential delay adverse event related to retroviral and lentiviral vectors for an extended period of time (bottom of second paragraph, right column, at page 4). Please note that safety issue is not one of the factors that determine obviousness of a claimed invention. Thus, in light of the totality of the cited prior art and the extensive discussions above, there is nothing that is unpredictable regarding at least to a method of treating cancer or killing cancer cells in a subject that is encompassed by the presently claimed invention.
B. The claimed methods exhibit superior and unexpected properties that could not be predicted from the teachings of the cited combination of references. Specifically, Applicant submitted data demonstrating the ability of the claimed method to rapidly and effectively reduce tumor burden within a subject via the Supplementary Figure 1 provided in this Amendment that showed the results of experiments in PBMC-humanized NSG mice with folate receptor positive (FR+) xenograft solid tumors. As shown in the Supplementary Figure 1, mice treated with a combination of the TagCAR vector (recombinant retroviral particles comprising a polynucleotide that encodes a receptor that binds to a hapten on UB-TT170 (an adaptor molecule comprising a targeting moiety that binds to a folate receptor and a hapten) and UB-TT170 saw rapid and effective reduction in tumor volume, and such results could not be predicted from the teachings of the cited combination of references, particularly in view of the high level of unpredictability in the field of in vivo cellular therapies as described above.
First, there is nothing that is unpredictable and/or unexpected result from the submitted data in the Supplementary Figure 1. Please refer to the above 103 rejection for details, along with Examiner’s responses to Applicant’s arguments in the preceding paragraphs.
Second, an ordinary skilled artisan would naturally expect that the combination of the TagCAR vector at 100e6TU dose and UB-TT170 is more effective than the combination of the TagCAR vector at 25eTU dose and UB-TT170, and both of these treatments are more effective than the lone treatment of TagCAR vector with 100e6TU or the lone treatment of UB-TT170 as shown in the Supplementary Figure 1. These results would have been predicted by an ordinary skilled artisan in light of the combined teachings of Low, Pule and Jensen as set forth in the above 103 rejection of record.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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
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