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 .
Claim Status
Claims 1-64, 66, 72-73, 88, and 91-92 have been cancelled; claims 65, 67-71, 75-76, 87, 89-90, 93, and 95 have been amended; and claims 96-102 have been newly added, as requested in the amendment filed on 04/01/2026. Following the amendment, claims 65, 67-71, 74-87, 89-90, and 93-102 are pending in the instant application.
Claims 77-86 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention in the Response filed 10/02/2024, there being no allowable generic or linking claim.
Claims 65, 67-71, 74-76, 87, 89-90, and 93-102 are under examination in the instant office action.
Claim Rejections - 35 USC § 112 - Withdrawn
Claim 75 was rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for lacking antecedent basis for the limitation “the vector”. Claim 75 has been amended to remove reference to “the vector”. As such, the rejection of claim 75 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
Claim Rejections - 35 USC § 102 - Withdrawn
Claims 65-66, 68-74, 76, 87, and 90-95 were rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by WO 2016/210447 A1 (previously cited on PTO-892; herein after referred to as "Wang").
Applicant has amended the method of independent claim 65 to require (i) a viral vector comprising a nucleic acid encoding the ABR, (ii) an exogenous inhibitory agent that interferes with the interaction of the antigen with an antigen binding domain of the ABR thereby reducing insertion of the nucleic acid encoding the ABR into a cell expressing the antigen. Wang does not anticipate such a method, as the inhibitory agent of Wang (i.e., the mask of the mCARs) is not an exogenous inhibitory agent nor does Wang read on interfering with nucleic acid insertion into a cell expressing an antigen. As such, the rejection of claims 5-66, 68-74, 76, 87, and 90-95 under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Wang is withdrawn.
Claim Rejections - 35 USC § 103 - Withdrawn
Claims 65-74, 76, 87, and 89-95 were rejected under 35 U.S.C. 103 as being unpatentable over WO 2016/210447 A1 (previously cited on PTO-892; herein after referred to as "Wang") in view of US 2018/0127510 A1 (previously cited on PTO-892; herein after referred to as “Liaudet-Coopman”), US 2002/0041898 A1 (previously cited on PTO-892; herein after referred to as “Unger”), US 2013/0095172 A1 (previously cited on PTO-892; herein after referred to as “Alavattam”), and non-patent literature by Li et. al. (Nature Methods, 2019, 16, 183-190; previously cited on PTO-892; herein after referred to as “Li”).
Claims 75 was rejected under 35 U.S.C. 103 as being unpatentable over WO 2016/210447 A1 (previously cited on PTO-892; herein after referred to as "Wang"), US 2018/0127510 A1 (previously cited on PTO-892; herein after referred to as “Liaudet-Coopman”), US 2002/0041898 A1 (previously cited on PTO-892; herein after referred to as “Unger”), US 2013/0095172 A1 (previously cited on PTO-892; herein after referred to as “Alavattam”), and non-patent literature by Li et. al. (Nature Methods, 2019, 16, 183-190; previously cited on PTO-892; herein after referred to as “Li”), as applied to claims 65-66, 68-74, 76, 87, and 90-95 above, and in further view of non-patent literature by Zhao-Emonet et. al. (The Journal of Gene Medicine, 2000, 2, 416-425; previously cited on PTO-892; herein after referred to as "Zhao-Emonet").
With regard to the above-listed claim rejections under 35 U.S.C. 103 over primary reference Wang and the additionally cited secondary references, it is noted that Applicant has amended the method of independent claim 65 to require (i) a viral vector comprising a nucleic acid encoding the ABR, (ii) an exogenous inhibitory agent that interferes with the interaction of the antigen with an antigen binding domain of the ABR thereby reducing insertion of the nucleic acid encoding the ABR into a cell expressing the antigen. Wang does not teach or suggest such a method, as the inhibitory agent of Wang (i.e., the mask of the mCARs) is not an exogenous inhibitory agent nor does Wang read on interfering with nucleic acid insertion into a cell expressing an antigen. The additionally cited references do not remedy these deficiencies. As such, the above-listed claim rejections under 35 U.S.C. 103 as being unpatentable over primary reference Wang are withdrawn.
Claims 65-66, 68-74, 76, 87-88, and 90-95 were rejected under 35 U.S.C. 103 as being unpatentable over non-patent literature by Ruella et. al. (Nature Medicine, 2018, 24, 1499-1503; previously cited on PTO-892; herein after referred to as “Ruella”) in view of WO 2016/210447 A1 (previously cited on PTO-892; herein after referred to as "Wang"), and Cordes et. al. (Molecular Therapy: Methods & Clinical Development, 2021, 21, 42-53; herein after referred to as “Cordes”).
Claims 67 and 89 were rejected under 35 U.S.C. 103 as being unpatentable over non-patent literature by Ruella et. al. (Nature Medicine, 2018, 24, 1499-1503; previously cited on PTO-892; herein after referred to as “Ruella”) and WO 2016/210447 A1 (previously cited on PTO-892; herein after referred to as "Wang"), as applied to claims 65-66, 68-74, 76, 87-88, and 90-95, and in further view of US 2013/0095172 A1 (previously cited on PTO-892; herein after referred to as “Alavattam”).
Claim 75 was rejected under 35 U.S.C. 103 as being unpatentable over non-patent literature by Ruella et. al. (Nature Medicine, 2018, 24, 1499-1503; previously cited on PTO-892; herein after referred to as “Ruella”) and WO 2016/210447 A1 (previously cited on PTO-892; herein after referred to as "Wang"), as applied to claims 65-66, 68-74, 76, 87-88, and 90-95 above, and in further view of non-patent literature by WO 2016/210447 A1 (previously cited on PTO-892; herein after referred to as "Wang"), as applied to claims 65-66, 68-74, 76, 87, and 90-95 above, and in further view of non-patent literature by Zhao-Emonet et. al. (The Journal of Gene Medicine, 2000, 2, 416-425; previously cited on PTO-892; herein after referred to as "Zhao-Emonet").
With regard to the above-listed claim rejections under 35 U.S.C. 103 over primary reference Ruella and the additionally cited secondary references, it is noted that Applicant has amended the method of independent claim 65 to require (i) a viral vector comprising a nucleic acid encoding the ABR, (ii) an exogenous inhibitory agent that interferes with the interaction of the antigen with an antigen binding domain of the ABR thereby reducing insertion of the nucleic acid encoding the ABR into a cell expressing the antigen. It is noted that Ruella does not teach or suggest how the accidental transduction of a cancer cell occurred, and does not teach/suggest a method to reduce such an occurrence by blocking ABR-antigen interactions using an exogenous agent. The additionally cited references do not remedy these deficiencies, nor do they establish the mechanism of accidental transduction observed by Ruella prior to the effective filing date of the instant invention. As such, the above-listed claim rejections under 35 U.S.C. 103 as being unpatentable over primary reference Ruella are withdrawn.
Double Patenting - Withdrawn
Claims 65-66, 68-74, 76, 87, and 90-95 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, and 15-20 of U.S. Patent No. 10,822,419 B2 (corresponds the US Patent associated with the Wang reference cited above; herein after referred to as “’419”) in view of WO 2016/210447 A1 (previously cited on PTO-892; herein after referred to as "Wang") and non-patent literature by Li et. al. (Nature Methods, 2019, 16, 183-190; herein after referred to as “Li”).
Claims 65-74, 76, 87, and 89-95 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, and 15-20 of ‘419 in view of WO 2016/210447 A1 (previously cited on PTO-892; herein after referred to as "Wang") in view of US 2018/0127510 A1 (herein after referred to as “Liaudet-Coopman”), US 2002/0041898 A1 (herein after referred to as “Unger”), US 2013/0095172 A1 (herein after referred to as Alavattam”), and non-patent literature by Li et. al. (Nature Methods, 2019, 16, 183-190; herein after referred to as “Li”).
Claim 75 was rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, and 15-20 of ‘419 in view of WO 2016/210447 A1 (previously cited on PTO-892; herein after referred to as "Wang"), US 2018/0127510 A1 (herein after referred to as “Liaudet-Coopman”), US 2002/0041898 A1 (herein after referred to as “Unger”), US 2013/0095172 A1 (herein after referred to as "Alavattam"), and non-patent literature by Li et. al. (Nature Methods, 2019, 16, 183-190; herein after referred to as “Li”), as applied to claims 65-66, 68-74, 76, 87, and 90-95 above, and in further view of non-patent literature by Zhao-Emonet et. al. (The Journal of Gene Medicine, 2000, 2, 416-425; herein after referred to as "Zhao-Emonet").
Claims 65-66, 68-74, 76, 87-88, and 90-95 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, and 15-20 of U.S. Patent No. 10,822,419 B2 (corresponds the US Patent associated with the Wang reference cited above; herein after referred to as”’419”) in view of non-patent literature by Ruella et. al. (Nature Medicine, 2018, 24, 1499-1503; previously cited on PTO-892; herein after referred to as “Ruella”), WO 2016/210447 A1 (previously cited on PTO-892; herein after referred to as "Wang"), and non-patent literature by Cordes et. al. (Molecular Therapy: Methods & Clinical Development, 2021, 21, 42-53; herein after referred to as “Cordes”).
Claims 67 and 89 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, and 15-20 of ‘419 in view of non-patent literature by Ruella et. al. (Nature Medicine, 2018, 24, 1499-1503; previously cited on PTO-892; herein after referred to as “Ruella”) and WO 2016/210447 A1 (previously cited on PTO-892; herein after referred to as "Wang"), as applied to claims 65-66, 68-74, 76, 87-88, and 90-95, and in further view of US 2013/0095172 A1 (herein after referred to as "Alavattam").
Claim 75 was rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, and 15-20 of ‘419 in view of non-patent literature by Ruella et. al. (Nature Medicine, 2018, 24, 1499-1503; previously cited on PTO-892; herein after referred to as “Ruella”) and WO 2016/210447 A1 (previously cited on PTO-892; herein after referred to as "Wang"), as applied to claims 65-66, 68-74, 76, 87-88, and 90-95 above, and in further view of non-patent literature by WO 2016/210447 A1 (previously cited on PTO-892; herein after referred to as "Wang"), as applied to claims 65-66, 68-74, 76, 87, and 90-95 above, and in further view of non-patent literature by Zhao-Emonet et. al. (The Journal of Gene Medicine, 2000, 2, 416-425; herein after referred to as "Zhao-Emonet").
As noted above, the cited prior art references alone do not teach/suggest independent claim 65 as currently amended, wherein the method has been amended to require (i) a viral vector comprising a nucleic acid encoding the ABR, (ii) an exogenous inhibitory agent that interferes with the interaction of the antigen with an antigen binding domain of the ABR thereby reducing insertion of the nucleic acid encoding the ABR into a cell expressing the antigen. The cited reference patent is the U.S. Patent corresponding to the cited Wang reference, wherein the claims are drawn to masked CARs. Wang (nor the claims of the reference patent) does not teach or suggest such a method instantly claimed, as the inhibitory agent of Wang (i.e., the mask of the mCARs) is not an exogenous inhibitory agent nor does Wang read on interfering with nucleic acid insertion into a cell expressing an antigen. It is further noted that Ruella does not teach or suggest how the accidental transduction of a cancer cell occurred, and does not teach/suggest a method to reduce such an occurrence by blocking ABR-antigen interactions using an exogenous agent. The additionally cited references do not remedy these deficiencies, nor do they establish the mechanism of accidental transduction observed by Ruella prior to the effective filing date of the instant invention. As such, the above-listed claim rejections under nonstatutory double patenting are withdrawn.
Claim Rejections - 35 USC § 112 - New as Necessitated by Amendment
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.
Claims 65, 67-71, 74-76, 87, 89-90, and 93 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. This is an ENABLEMENT rejection.
The Breadth of the Claims
Claim 65 recites a method for reducing the insertion of a nucleic acid encoding an antigen binding receptor (ABR) into a cell expressing an antigen that is targeted by the ABR comprising contacting the cell with a viral vector comprising a nucleic acid encoding the ABR in the presence of an exogenous inhibitory agent, wherein the exogenous inhibitory agent interferes with the interaction of an antigen binding domain of the ABR and the antigen thereby reducing insertion of the nucleic acid encoding the ABR into the cell expressing the antigen. Claim 87 is directed to a composition comprising a viral vector comprising a nucleic acid encoding an antigen binding receptor (ABR) construct and an inhibitory agent that interferes with blocks the interaction of an antigen binding domain of the ABR and the antigen. The vector of the claims is not indicated as enveloped and the ABR is not surface expressed, and as such the method and composition are not enabled as there is no way to interfere with the viral vector because there is no association of it with a surface expressed ABR.
The State of the Prior Art/ Level of Predictability in the Art
As demonstrated by Chen et. al. (Current Protocols in Mouse Biology, 2018, e58, Pages 1-7; herein after referred to as “Chen”), viral vectors are established in the art as a promising tool for effective delivery of genetic material into cells by taking advantage of the natural ability of a virus to deliver a genetic payload into cels while being genetically modified such that their ability to replicate is crippled or removed (Abstract). Adeno-associated viruses (AAV) are considered nonpathogenic parvoviruses composed of a 4.7-kb single-stranded DNA encapsulated in a non-enveloped, icosahedral capsid (size 20 to 25 nm in diameter). The viral genome is composed of three genes, Rep, Cap, and AAP, flanked by inverted terminal repeats (ITRs) that function as the viral origin of replication and the packaging signal (Page 1, Column 2, Biology of AAV). Retroviruses are single-stranded RNA viruses that package two copies of positive strand RNA surrounded by the capsid and envelope (80 to 120 nm in diameter) and the RNA genome of gamma retroviruses encodes the gag, pol, and env genes flanked by long terminal repeats (LTRs), which function as enhancers and promoters; the gag gene encodes the structural protein, the pol gene encodes the reverse transcriptase and integrase, and the env gene encodes the envelope proteins (Page 3, Biology of Retroviruses and Lentiviruses). Lentiviruses, a subcategory of the retrovirus family, are known as complex retroviruses based on the details of the viral genome; in addition to genes found in retroviruses, lentiviruses carry an additional six genes encoding the accessory proteins tat, rev, vpr, vpu, nef, and vif, which encode proteins important for viral replication, binding, infection, and release (Id.). Adenoviruses are non-enveloped and have an icosahedral protein capsid (90 nm in diameter) encompassing a double-stranded DNA genome; the genomic DNA of Ad ranges from 26 to 45 kb and is flanked by two inverted terminal repeats (ITR) (Page 4, Column 2, Biology of Adenovirus). Buchholz et. al. (Trends in Biotechnology, 2015, 33(12), Pages 777-790; herein after referred to as “Buchholz”) discloses advances in gene transfer technology which enables Recent progress in gene transfer technology enables the delivery of genes precisely to the application-relevant cell type ex vivo on cultivated primary cells or in vivo on local or systemic administration; gene vectors based on lentiviruses or adeno-associated viruses can be engineered such that they use a cell surface marker of choice for cell entry instead of their natural receptors wherein binding to the surface marker is mediated by a targeting ligand displayed on the vector particle surface, which can be a peptide, single-chain antibody, or designed ankyrin repeat protein and examples include vectors that deliver genes to specialized endothelial cells or lymphocytes, tumor cells, or particular cells of the nervous system with potential applications in gene function studies and molecular medicine (Abstract). Receptor targeting of viral vectors has made substantial progress during the past years. The list of receptors and corresponding cell types that can be successfully targeted with LV or AAV vectors is continuously growing (Tables 1 and 2) and it has become clear that these vectors will be instrumental to achieve in vivo gene therapy upon local and especially systemic vector application; while proof of principle for some targets has been demonstrated, future efforts will focus on developing vectors for further important target cell types and on improving the system to make clinical applications possible (Pages 786-787, Concluding Remarks and Future Perspectives).
The Amount of Direction Provided by the Inventor/Existence of Working Examples
Paragraph 0026 of the instant specification indicates that the disclosure is based on the discovery that ABR (e.g., a CAR, TFP, TAC etc.) polypeptides get inserted into the envelope of lentiviral vectors when the lentivirus is being produced in the producer cell line (e.g., 293FT cells). For example, a CD19-CAR polypeptide can be expressed by the producer cell line and translocated to the cellular membrane, where upon budding of the lentiviral vectors the CD19-CAR gets inserted into the envelope of a lentivirus containing the CD19 CAR polynucleotide. The resulting lentivirus can then enter the target cells through two mechanisms: (1) via the fusion of the envelop protein (e.g., VSVG envelop glycoprotein in case of VSVG pseudotyped virus) to its receptor and (2) via attachment of the antigen binding receptor (ABR) polypeptide to its target antigen (e.g., CD19 in case of a CD19 targeted CAR polypeptide). In the case of T cells, only the first mechanism is operative. However, in case of a cancer cell, e.g., a leukemia cell or lymphoma cell; e.g., a CD19-expressing leukemia or lymphoma cell, both the mechanisms are at play, resulting in preferential insertion of CAR construct into cancer cells (e.g., leukemia cells or lymphoma cells). The disclosure provides methods and compositions to inhibit the accidental insertion of a ABR (e.g., a CAR, TFP, TAC etc.) into a cell, e.g., a cancer cell, by including an agent, such as an antibody, an antibody fragment, a vHH domain, a non-immunoglobulin antigen binding domain, a soluble receptor, or Protein L or a fragment thereof, that blocks the interaction of the antigen binding domain of the recombinant antigen binding receptor polypeptide (e.g., CAR polypeptide, e.g., CD19 scFV fragment comprising the CD19 CAR) with the antigen (e.g., CD19) being targeted by the ABR (e.g., a CAR, TFP, TAC etc.). At Paragraph 0029, the specification discloses an embodiment of a method, comprising contacting an ex vivo cell population with an exogenous inhibitory agent that is a soluble antigen or fragment thereof that is a cognate to the binding domain of the ABR (e.g., a CAR, TFP etc.) and inhibits the interaction of an ABR (e.g., a CAR, TFP etc.) present on the envelope of the viral vector with its binding partner on cells in the ex vivo population of cells. Furthermore, it is noted that all of the working Examples of the instant disclosure only use enveloped viral vectors, wherein surface display of ABRs is possible; there are no examples demonstrating that non-enveloped vectors comprising nucleic acids encoding an ABR surface display said ABR such that the interaction of the ABR and its antigen target could be interfered with.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to use and/or make compositions comprising a viral vector comprising a nucleic acid encoding an antigen binding receptor (ABR) construct and an inhibitory agent that serves to interfere with the interaction of an antigen binding domain of the ABR and the antigen thereby preventing accidental insertion of the nucleic acid encoding the ABR into a cell expressing the antigen targeted by the ABR.
Claims 96-102 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 using an exogenous inhibitory agent that targets the antigen targeted by the ABR to reduce insertion of a nucleic acid encoding an ABR into a cell expressing the antigen, wherein the nucleic acid encoding the ABR is comprised within an , does not reasonably provide enablement for using an exogenous inhibitory agent that targets the antigen targeted by the ABR to reduce insertion of a nucleic acid encoding an ABR into a cell expressing the antigen, wherein the nucleic acid encoding the ABR is comprised within a . The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. This is a SCOPE OF ENABLEMENT rejection.
The Breadth of the Claims
Claim 96 recites a method for reducing the insertion of a nucleic acid encoding an antigen binding receptor (ABR) into a cell expressing an antigen that is targeted by the ABR, wherein a viral vector comprising the nucleic acid encoding the ABR is produced using packaging cells, the method comprising one or more of the following: (a) contacting the cell with the viral vector comprising the nucleic acid encoding the ABR in the presence of an exogenous inhibitory agent, wherein the exogenous inhibitory agent interferes with the interaction between an antigen binding domain of the ABR and the antigen, wherein the cell is contacted with the exogenous inhibitory agent before and/or during the step of contacting the cell with the viral vector; (b) reducing or eliminating expression of the ABR on a surface of the packaging cells that are used to produce the viral vector; (c) co-expressing, in the packaging cells that are used to produce the viral vector, the antigen or a fragment thereof that is recognized by the antigen binding domain of the ABR, or a membrane- anchored binding molecule that binds to the antigen binding domain of the ABR, such that the ABR expressed on a surface of the viral vector is bound by the co-expressed antigen, fragment thereof, or membrane-anchored binding molecule; (d) reducing or eliminating expression of the ABR on an envelope of the viral vector; thereby reducing the insertion of the nucleic acid encoding the ABR into the cell expressing the antigen.. The vector of 96(a) is not indicated as enveloped and the ABR is not surface expressed, and as such the full scope of the method is not enabled as there is no way to interfere with the viral vector because there is no association of it with a surface expressed ABR.
The State of the Prior Art/Level of Predictability in the Art
As demonstrated by Chen et. al. (Current Protocols in Mouse Biology, 2018, e58, Pages 1-7; herein after referred to as “Chen”), viral vectors are established in the art as a promising tool for effective delivery of genetic material into cells by taking advantage of the natural ability of a virus to deliver a genetic payload into cels while being genetically modified such that their ability to replicate is crippled or removed (Abstract). Adeno-associated viruses (AAV) are considered nonpathogenic parvoviruses composed of a 4.7-kb single-stranded DNA encapsulated in a non-enveloped, icosahedral capsid (size 20 to 25 nm in diameter). The viral genome is composed of three genes, Rep, Cap, and AAP, flanked by inverted terminal repeats (ITRs) that function as the viral origin of replication and the packaging signal (Page 1, Column 2, Biology of AAV). Retroviruses are single-stranded RNA viruses that package two copies of positive strand RNA surrounded by the capsid and envelope (80 to 120 nm in diameter) and the RNA genome of gamma retroviruses encodes the gag, pol, and env genes flanked by long terminal repeats (LTRs), which function as enhancers and promoters; the gag gene encodes the structural protein, the pol gene encodes the reverse transcriptase and integrase, and the env gene encodes the envelope proteins (Page 3, Biology of Retroviruses and Lentiviruses). Lentiviruses, a subcategory of the retrovirus family, are known as complex retroviruses based on the details of the viral genome; in addition to genes found in retroviruses, lentiviruses carry an additional six genes encoding the accessory proteins tat, rev, vpr, vpu, nef, and vif, which encode proteins important for viral replication, binding, infection, and release (Id.). Adenoviruses are non-enveloped and have an icosahedral protein capsid (90 nm in diameter) encompassing a double-stranded DNA genome; the genomic DNA of Ad ranges from 26 to 45 kb and is flanked by two inverted terminal repeats (ITR) (Page 4, Column 2, Biology of Adenovirus). Buchholz et. al. (Trends in Biotechnology, 2015, 33(12), Pages 777-790; herein after referred to as “Buchholz”) discloses advances in gene transfer technology which enables Recent progress in gene transfer technology enables the delivery of genes precisely to the application-relevant cell type ex vivo on cultivated primary cells or in vivo on local or systemic administration; gene vectors based on lentiviruses or adeno-associated viruses can be engineered such that they use a cell surface marker of choice for cell entry instead of their natural receptors wherein binding to the surface marker is mediated by a targeting ligand displayed on the vector particle surface, which can be a peptide, single-chain antibody, or designed ankyrin repeat protein and examples include vectors that deliver genes to specialized endothelial cells or lymphocytes, tumor cells, or particular cells of the nervous system with potential applications in gene function studies and molecular medicine (Abstract). Receptor targeting of viral vectors has made substantial progress during the past years. The list of receptors and corresponding cell types that can be successfully targeted with LV or AAV vectors is continuously growing (Tables 1 and 2) and it has become clear that these vectors will be instrumental to achieve in vivo gene therapy upon local and especially systemic vector application; while proof of principle for some targets has been demonstrated, future efforts will focus on developing vectors for further important target cell types and on improving the system to make clinical applications possible (Pages 786-787, Concluding Remarks and Future Perspectives).
The Amount of Direction Provided by the Inventor/Existence of Working Examples
Paragraph 0026 of the instant specification indicates that the disclosure is based on the discovery that ABR (e.g., a CAR, TFP, TAC etc.) polypeptides get inserted into the envelope of lentiviral vectors when the lentivirus is being produced in the producer cell line (e.g., 293FT cells). For example, a CD19-CAR polypeptide can be expressed by the producer cell line and translocated to the cellular membrane, where upon budding of the lentiviral vectors the CD19-CAR gets inserted into the envelope of a lentivirus containing the CD19 CAR polynucleotide. The resulting lentivirus can then enter the target cells through two mechanisms: (1) via the fusion of the envelop protein (e.g., VSVG envelop glycoprotein in case of VSVG pseudotyped virus) to its receptor and (2) via attachment of the antigen binding receptor (ABR) polypeptide to its target antigen (e.g., CD19 in case of a CD19 targeted CAR polypeptide). In the case of T cells, only the first mechanism is operative. However, in case of a cancer cell, e.g., a leukemia cell or lymphoma cell; e.g., a CD19-expressing leukemia or lymphoma cell, both the mechanisms are at play, resulting in preferential insertion of CAR construct into cancer cells (e.g., leukemia cells or lymphoma cells). The disclosure provides methods and compositions to inhibit the accidental insertion of a ABR (e.g., a CAR, TFP, TAC etc.) into a cell, e.g., a cancer cell, by including an agent, such as an antibody, an antibody fragment, a vHH domain, a non-immunoglobulin antigen binding domain, a soluble receptor, or Protein L or a fragment thereof, that blocks the interaction of the antigen binding domain of the recombinant antigen binding receptor polypeptide (e.g., CAR polypeptide, e.g., CD19 scFV fragment comprising the CD19 CAR) with the antigen (e.g., CD19) being targeted by the ABR (e.g., a CAR, TFP, TAC etc.). At Paragraph 0029, the specification discloses an embodiment of a method, comprising contacting an ex vivo cell population with an exogenous inhibitory agent that is a soluble antigen or fragment thereof that is a cognate to the binding domain of the ABR (e.g., a CAR, TFP etc.) and inhibits the interaction of an ABR (e.g., a CAR, TFP etc.) present on the envelope of the viral vector with its binding partner on cells in the ex vivo population of cells. Furthermore, it is noted that all of the working Examples of the instant disclosure only use enveloped viral vectors, wherein surface display of ABRs is possible; there are no examples demonstrating that non-enveloped vectors comprising nucleic acids encoding an ABR surface display said ABR such that the interaction of the ABR and its antigen target could be interfered with.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to use an exogenous inhibitory agent to reduce the insertion of a viral vector comprising a nucleic acid encoding an antigen binding receptor (ABR) construct into a cell expressing that antigen targeted by the ABR wherein the exogenous inhibitory agent serves to interfere with the interaction of an antigen binding domain of the ABR, which is not surface expressed, with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples commensurate in scope with the claimed invention.
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 67, 89, and 96-102 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.
Regarding claims 67, 89, and 97 the phrase "optionally" renders the claims indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. As amended, claims 67, 89, and 97 each recite “optionally an Fc chimera of the antigen”; it is unclear as to if an Fc chimera of the antigen is intended to be limiting, or if it is merely an exemplary exogenous inhibitory agent. See MPEP § 2173.05(d).
Claim 96 recites the limitation "the cell" at lines 5 and 7-9 (see 96(a)). There is insufficient antecedent basis for this limitation in the claim. It is unclear if “the cell” is intended to refer to the cell expressing an antigen that is targeted by the ABR or the packaging cells (see lines 1-4 of claim 96). As such, the limitation “the cell” lacks antecedent basis and renders the claim indefinite.
Regarding claim 101 the phrase "optionally" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. Claim 101 recites “optionally wherein the agent is polybrene or retronectin”; it is unclear as to if polybrene or retronectin are intended to be limiting, or if they are merely exemplary exogenous inhibitory agents. See MPEP § 2173.05(d).
With regard to claim 98, the claim recites the method of claim 96, wherein the membrane-anchored binding molecule of (c) is a membrane-anchored form of Protein L or a fragment thereof that binds to κ light chains of an antibody, a membrane-anchored form of an anti-idiotype antibody targeting an scFv region of the ABR, or a membrane-anchored form of the antigen or a fragment thereof; however, it is noted that claim 96 does not necessarily require 96(c), but rather one or more of 96(a)-(c), rendering claim 98 ambiguous in the context of claim 96 from which it depends.
Regarding claim 100, the claim recites the method of claim 96, wherein the reducing or eliminating of expression of the ABR in (b) or (d) is achieved by controlling expression of the ABR at a transcriptional, post- transcriptional, translational, or post-translational level, or by inducing degradation of the ABR polypeptide; however, claim 96 does not necessarily require 96(b) or (d), but rather one or more of 96(a)-(c), rendering claim 100 ambiguous in the context of claim 96 from which it depends.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 98 and 100 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 98 and 100 are of improper dependent form as they do not necessarily limit the subject matter of the claim 96, from which each claim depends. Claim 98 recites the method of claim 96, wherein the membrane-anchored binding molecule of (c) is a membrane-anchored form of Protein L or a fragment thereof that binds to κ light chains of an antibody, a membrane-anchored form of an anti-idiotype antibody targeting an scFv region of the ABR, or a membrane-anchored form of the antigen or a fragment thereof; however, it is noted that claim 96 does not necessarily require 96(c), but rather one or more of 96(a)-(c), and as such claim 98 does not necessarily serve to further limit the subject matter of claim 96. Similarly, claim 100 recites the method of claim 96, wherein the reducing or eliminating of expression of the ABR in (b) or (d) is achieved by controlling expression of the ABR at a transcriptional, post- transcriptional, translational, or post-translational level, or by inducing degradation of the ABR polypeptide; however, claim 96 does not necessarily require 96(b) or (d), but rather one or more of 96(a)-(c), and as such claim 100 does not necessarily serve to further limit the subject matter of claim 96. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Response to Arguments
Applicant’s arguments with respect to claim(s) 65, 67-71, 74-76, 87, 89-90, and 93-95 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument. Furthermore, specifically with pertaining to the arguments with regard to Applicant’s discovery that CAR display on the viral envelope creates an additional, significant entry pathway for antigen-presenting cells, it is noted that the features upon which applicant relies (i.e., surface expression of an ABR) are not recited in and/or required by the rejected claims as amended, including the newly added claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Furthermore, the currently pending claims do not require that the recited viral vector display a CAR at its surface (i.e., on the viral envelope), and as such the argument regarding discovery that CAR display on the viral envelope creates an additional, significant entry pathway for antigen-presenting cells is not fully commensurate in scope with the instant claims as amended, including the newly added claims.
Conclusion
Claims 65, 67-71, 74-87, 89-90, and 93-102 are pending. Claims 77-86 are withdrawn. Claims 65, 67-71, 74-76, 87, 89-90, and 93-102 are rejected. No claims are 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.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/Laura B Goddard/Primary Examiner, Art Unit 1642
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