DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claim 17 has been canceled. Claim 21 has been added. Claims 1-16, 18-21 are pending.
Election/Restriction
The restriction between Groups I-IV in parent application 16153211 sent 4-17-20 was withdrawn upon allowing claims directed towards a vector (Group I; claim 1), a viral packaging system comprising the vector (Group II, claim 4), an isolated cell (Group III, claim 7) and a method of treatment (Group IV, claim 12-14) in ‘211 on 10-5-20. The restriction was withdrawn in view of application 14776673, now US Patent 9663564, which allowed a vector as well as a viral packaging system comprising the vector. The withdrawn restriction was noted in parent application 17168645, now US Patent 11939591.
Claims 1-16, 18-21 are under consideration.
Applicant's arguments filed 2-6-26 have been fully considered but they are not persuasive.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim objections
Claim 14 repeats peripheral artery disease or limb ischemia in the preamble. Please simplify.
It is unclear when limb ischemia is “critical” in claim 14. Delete “critical”.
Use of “and/or” is confusing in claim 14. Using “or” encompasses ---and---.
Use of “effective amount” along with attempting to say a therapeutic result occurs in claim 14 is confusing. Just say the therapeutic effect.
The phrase “mammalian patient” in claim 14 can be written more simply as ---mammal---.
The phrase “thereby treating…” in claim 14 is not a clear, positive functional limitation of the “administering”. The phrase “such that symptoms of the peripheral artery disease or limb ischemia improve” would be a clear, positive functional limitation of the “administering” because it MUST occur and because the symptoms of the peripheral artery disease or limb ischemia must be ameliorated.
The phrase by “intravenous injection or intramuscular injection” in claim 14 can be written more simply as ---intravenously or intramuscularly---.
The phrase “mammalian patient in need thereof” does not have a nexus with the “mammalian patient having peripheral artery disease or critical limb ischemia” in claim 14.
Claim 14 can be written more simply and accurately as ---A method for treating peripheral artery disease or limb ischemia, the method comprising: administering the mesenchymal stem cell of claim 10 to a mammal that has peripheral artery disease or limb ischemia intravenously or intramuscularly such that symptoms of the peripheral artery disease or limb ischemia improve---. Various improvements are shown in para 192
Claim Rejections - 35 USC § 112
Written Description
Claims 1-16, 18-20 remain and claim 21 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Withdrawn rejection
The rejection regarding claims 9-13, 19, 20 has been withdrawn. The claims are drawn to an isolated mammalian cell comprising the vector of claim 1 wherein the vector is a lentiviral vector. While the cell must be transduced by a lentiviral particle, the cell contains the “lentiviral vector” of claim 1 once the contents of the lentiviral particle have entered the genome of the cell. Therefore, this language is acceptable.
Pending rejections
A) Claim 1 lacks written description other than a composition comprising a lentiviral vector comprising a constitutive promoter, a nucleic acid encoding VEGF 165A isoform, and a WPRE enhancer. Claim 1 is drawn to a vector comprising: a polynucleotide comprising following operatively linked to each other: a constitutive promoter; a nucleic acid encoding a VEGF 165 isoform protein; and a WPRE enhancer comprising nucleotides 7564-8160 of SEQ ID NO: 23 or a functional complement thereof having at least 90% sequence identity to SEQ ID NO: 23.
The specification teaches a lentiviral vector comprising a constitutive promoter, a nucleic acid encoding a VEGF 165A isoform protein, and a WPRE enhancer (Examples). The specification teaches the term “lentiviral vector” refers exclusively to a viral particle capable of introducing exogenous nucleic acid into the cell (para 75-76). The specification conflates lentiviral plasmids and lentiviral vectors with lentiviral particles throughout the disclosure (para 77-78, 112) and discusses packaging systems for making viral particles (para 131-144). The specification does not correlate the lentiviral vector to any plasmid without lentiviral elements as broadly encompassed by claim 1. The specification does not correlate lentiviral vectors to any retroviral, AAV, adenoviral, baculoviral, etc. vector as broadly encompassed by claim 1. The specification does not correlate VEGF 165A isoform to VEGF 165B, VEGF 165C, or any other VEGF 165 isoform. The specification lacks written description for any WPRE enhancer “comprising nucleotides 7564-8160 of SEQ ID NO: 23 or a functional complement thereof having at least 90% sequence identity to SEQ ID NO: 23” as required in claim 1. The phrase does not make sense because “a functional complement thereof having at least 90% sequence identity to SEQ ID NO: 23” is broader than “nucleotides 7564-8160 of SEQ ID NO: 23” and has a different scope. The specification does not teach any “functional equivalents” of nucleotides 7564-8160 SEQ ID NO: 23. The specification does not teach any sequences with 90% identity to SEQ ID NO: 23 that are “functional equivalents”. The specification does not teach an assay for determining WPRE “functional equivalents” of SEQ ID NO: 23 or nucleotides 7564-8160 SEQ ID NO: 23.
The specification does not teach nucleotides 7564-8160 of SEQ ID NO: 23 are a WPRE as required in claims 1 and 8. Pg 10, para 45, says nucleotides 7564-8160 SEQ ID NO: 23 is mRNA (“mRNA <7564..>8160” – line 8 of para 45).
Accordingly, the concept lacks written description of claim 1 other than a lentiviral vector comprising a constitutive promoter, a nucleic acid encoding VEGF 165A isoform, and a WPRE enhancer.
B) The specification lacks written description for claim 7 other than a lentiviral packaging system comprising a lentiviral vector, a packaging plasmid, and an envelope plasmid. Claim 7 is drawn to a viral packaging system, but claim 1 does not require the vector is a viral vector. There is no way to package viral particles without the vector of claim 1 being a viral vector. The specification is limited to a lentiviral vector for reasons set forth above. Accordingly, the concept lacks written description other than a lentiviral vector.
C) The specification lacks written description any “biological equivalent thereof” of VEGF 165 as broadly encompassed by claim 13 other than VEGF 165A isoform. The specification does not correlate VEGF 165A isoform to VEGF 165B, VEGF 165C, or any other VEGF 165 isoform. The specification does not correlate The specification does not correlate VEGF 165A isoform to any “biological equivalent thereof”. Accordingly, the concept lacks written description.
D) Claim 14 drawn to a method for treating peripheral artery disease and/or critical limb ischemia in a patient in need thereof comprising administering to the patient an effective amount of an isolated mesenchymal comprising a lentiviral vector comprising a polynucleotide comprising the following operatively linked to each other: a constitutive promoter, a nucleic acid encoding VEGF 165 isoform, and a WPRE enhancer.
Claim 14 encompasses treating a mammal with peripheral artery disease/critical limb ischemia by promoting wound healing/rate of angiogenesis/vascularization, decreasing wound size/time to wound, or salvaging a limb. Claim 14 is limited to intravascular or intramuscular delivery of MSCs comprising a lentiviral vector encoding VEGF operably linked to a constitutive promoter. But the site of administration does not have to be the site of peripheral artery disease or limb ischemia.
Claim 15 encompasses treating any mammal “in need thereof” by promoting wound healing/rate of angiogenesis/vascularization, decreasing wound size/time to wound, or salvaging a limb. Claim 15 is limited to intravascular or intramuscular delivery of MSCs comprising a lentiviral vector encoding VEGF operably linked to a constitutive promoter. But the site of administration does not have to be a site of disease.
Claim 16 encompasses treating any mammal with peripheral artery disease or critical limb ischemia by promoting wound healing/rate of angiogenesis/vascularization, decreasing wound size/time to wound, or salvaging a limb. Claim 16 is limited to intravascular or intramuscular delivery of MSCs comprising a lentiviral vector encoding VEGF operably linked to a constitutive promoter. But the site of administration does not have to be the site of peripheral artery disease or limb ischemia.
VEGF gene therapy
Morse (Current opinion in molecular therapeutics, (2001 Feb) Vol. 3, No. 1, pp. 97-101) summarized the state of the art of VEGF gene therapy (pg 100; Clinical”). In particular, it was known to administer plasmid DNA encoding VEGF in liposomes during coronary angioplasty (Laitinen), naked plasmid DNA encoding VEGF165 intramuscularly into an ischemic limb (Baumgartner), plasmid DNA encoding VEGF into the myocardium through a thoracotomy to treat angina (Symes), and plasmid or adenovirus encoding VEGF into arteries during angioplasty (Makinen).
Baumgartner (Progress in Gene Therapy (2004), 65-106. Editor(s): Bertolotti, Roger; Ozawa, Keiya; Hammond, H. Kirk. Publisher: VSP BV, Zeist, Neth) taught VEGF gene therapy for critical limb ischemia. In particular, Baumgartner taught the potential for using bone marrow stem cells for ex vivo gene transfer of VEGF (pg 89-90).
Symes (Progress in Gene Therapy (2004), 107-131. Editor(s): Bertolotti, Roger; Ozawa, Keiya; Hammond, H. Kirk. Publisher: VSP BV, Zeist, Neth) taught angiogenic VEGF gene therapy for refractory angina pectoris and taught the potential for using bone marrow stem cells for ex vivo gene transfer of VEGF (pg 127).
Song (Jiangsu Yiyao (2005), 31(5), 360-362) injected adenovirus encoding VEGF165 intramuscularly to rat ischemic hind limb enhanced mobilization of CD117 marrow stem cells to ischemic tissue where they differentiate into endothelial cells and cause neovascularization.
7223740, 7563777, and 8580755 taught VEGF165 gene therapy and suggested ex vivo gene therapy.
Transfecting bone marrow stem cells with a vector encoding VEGF165
Bai (Sichuan da xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition, (2005 Jul) Vol. 36, No. 4, pp. 468-70) transfected bone marrow stromal cells with a plasmid encoding VEGF165 which serves as the basis for the next step of revascularization of bone tissue engineering.
Gao (Jiefangjun Yixue Zazhi (2009), 34(2), 192-195) transfected bone marrow stromal cells with an adenovirus encoding VEGF165 which may provide a novel approach to local gene therapy of bone tissue engineering.
Bone marrow stem cell therapy for angiogenesis
Li (Zhongguo Zuzhi Gongcheng Yanjiu Yu Linchuang Kangfu (2007), 11(28), 5574-5579) transplanted bone marrow stem cells into patients with myocardial infarction which relieved ventricular remodeling and improved heart function.
Ex vivo VEGF gene therapy
Iwaguro (Circulation, 2002, Vol. 105, pg 732-738) transfected bone marrow derived endothelial progenitor cells (EPCs) with an adenoviral vector encoding VEGF164 and transplanted them intravenously to mice having ischemia (pg 733). The adenoviral vector inherently had a promoter that regulated expression of the VEGF164 as evidenced by expression.
Chen (European J. Clin. Investigation, 2005, Vol. 35, pg 677-686) administered cord blood stem cells comprising an AAV vector encoding VEGF165 operably linked to a CMV promoter and IRES and other elements for "high-level gene expression” in mammalian cells (pg 678, col. 2, 1st full paragraph) to mice intramycoardially to treat myocardial infarction (pg 679, 1st paragraph).
Hou (Biotechnology Letters (2009), 31(8), 1183-1189) transfected bone marrow stromal cells (BMSCs) with an adenoviral vector encoding VEGF165 and administered the cells subcutaneously to a mouse model of angiogenesis and osteogenesis or a rabbit model of bone defect repair (pg 1184, col. 1).
Chen (International Journal of Artificial Organs, (DEC 2011) Vol. 34, No. 12, pp. 1137-1146) transfected endothelial progenitor cells with an adenoviral vector encoding full length VEGF and transplanted the cells into the bladder of pigs which significantly enhanced neovascularization (abstract).
Unpredictability of gene therapy
The route of administration, vector, promoter, or level of expression required to target the desired tissue and obtain the desired clinical results using gene therapy were unpredictable at the time of filing. Miller (1995, FASEB J., Vol. 9, pages 190-199) review the types of vectors available for in vivo gene therapy, and conclude that "for the long-term success as well as the widespread applicability of human gene therapy, there will have to be advances...targeting strategies outlined in this review, which are currently only at the experimental level, will have to be translated into components of safe and highly efficient delivery systems" (page 198, column 1). Deonarain (1998, Expert Opin. Ther. Pat., Vol. 8, pages 53-69) indicate that one of the biggest problems hampering successful gene therapy is the "ability to target a gene to a significant population of cells and express it at adequate levels for a long enough period of time" (page 53, first paragraph). Deonarain reviews new techniques under experimentation in the art, which show promise, but states that such techniques are even less efficient than viral gene delivery (see page 65, first paragraph under Conclusion section). Verma (Sept. 1997, Nature, Vol. 389, pages 239-242) reviews vectors known in the art for use in gene therapy and discusses problems associated with each type of vector. The teachings of Verma indicate a resolution to vector targeting has not been achieved in the art (see entire article). Verma also teaches appropriate regulatory elements may improve expression, but it is unpredictable what tissues such regulatory elements target (page 240, sentence bridging columns 2 and 3). Crystal (1995, Science, Vol. 270, page 404-410) also reviews various vectors known in the art and indicates that "among the design hurdles for all vectors are the need to increase the efficiency of gene transfer, to increase target specificity and to enable the transferred gene to be regulated" (page 409). These references continue to reflect the state of the art at the effective time of filing (2012). Therefore, the state of the art at the time of gene therapy was that the route of administration, vector, promoter, or level of expression required to target a specific tissue of interest such that a desired clinical effect was obtained using gene therapy was unpredictable.
Pfeifer (Annu. Rev. Genomics. Hum. Genet. 2001, Vol. 2, pg 177-211; pg. 177, 1st paragraph) taught “though gene therapy holds great promise for the achievement of this task, the transfer of genetic material into higher organisms still remains an enormous technical challenge.” Johnson-Saliba (Curr. Drug. Targets, 2001, Vol. 2, pg 371-399) concurs stating that “although thousands of patients have been involved in clinical trials for gene therapy, using hundreds of different protocols, true success has been limited. A major limitation of gene therapy approaches, especially when non-viral vectors are used, is the poor efficiency of DNA delivery” (Abstract). Such problems with delivery continue to plague the field of gene therapy. Shoji (Current Pharmaceutical Design, 2004, Vol. 10, pg 785-796) characterized the current state of the art as the "tragic failure of gene therapy" because of poor delivery of gene based-medicines due to the lack of an appropriate vector that "fulfills the necessary requirements, including high transfection efficiency, non-toxicity, non-pathogenicity, non- immunogenicity, [and] non-tumorgenicity."
Teachings in the specification
Applicants isolated mesenchymal stem cells from umbilical cord blood (pg 50, paragraph 171) and transfected them with a lentiviral vector encoding VEGF165A operably linked to a CMV promoter (pg 50, paragraph 172).
Pg 58, paragraph 191, describes the overexpression of VEGF from MSCs enhanced migration of endothelial cells and blood flow after hind limb ischemia but does not teach the structure of the MSCs, the vector, promoter or route of administration.
Example 2 (pg 62) suggests administering MSCs expressing VEGF165A to treat ischemia but the example is prophetic. The example does not clearly teach the structure of the vector, promoter, or route of administration required to treat ischemia. See also pg 68, paragraph 225, of Example 2.
Example 3 relates to MSC expansion and transduction (pg 71).
Applicants have provided no greater assistance in methods of VEGF gene therapy than the art at the time of filing. In fact, it appears that the examples are all prophetic, thus requiring those of skill to rely on the art at the time of filing for enablement in view of the unpredictability of gene therapy using lentiviral vectors. The specification lacks written description for injecting the MSCs intravenously anywhere such that ischemia in a limb would be treated or be able to treat wound healing in the brain by crossing the blood brain barrier. The specification and the art at the time of filing do not teach that pancreatic, muscle, lung, skin, heart, reproductive, etc… cells containing the “vector” of claim 1 would treat the diseases listed other than marrow stromal cells. The specification fails to correlate the CMV promoter suggested to any other constitutive promoter, intravenous administration of genetically modified MSC (pg 69, line 3) to intramuscular injection such that the MSCs and exogenous VEGF expression would be targeted to cells of interest or that VEGF would be expressed to therapeutic levels in the desired tissue as broadly encompassed by claim 14-16. Given the unpredictability of the specific combination of target tissue, protein, promoter, route of administration and dosage required to obtain a therapeutic effect using gene therapy taken with the limited teachings in the specification, the specification lacks written description for expressing VEGF in isolated MSCs, using any constitutive promoter, or administering the MSCs intravenously or intramuscularly such that symptoms of peripheral artery disease or limb ischemia would be treated as broadly encompassed by claim 14-16 other than those methods known in the art at the time of filing.
Response to arguments
Applicants’ argument is noted but is not persuasive for reasons set forth above.
Enablement
Claims 1-16, 18-20 remain and claim 21 is 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 composition comprising a plasmid encoding VEGF operably linked to a constitutive promoter and a WPRE enhancer, a packaging plasmid, and an envelope plasmid (claim 1); an isolated mammalian packaging cell comprising the composition of claim 1 (claim 9); an isolated mammalian cell comprising a nucleic acid sequence encoding VEGF operably linked to a constitutive promoter and a WPRE enhancer (claim 9); inducing angiogenesis in a mammal by administering a cell comprising a vector encoding VEGF operably linked to a constitutive promoter to an area of ischemia in a mammal such that treatment occurs, does not reasonably provide enablement for the “vector” of claim 1 as broadly claimed; any cell as broadly encompassed by claim 9; administering any isolated cell comprising the “vector” (a packaging system) of claim 1 for treatment (claim 14); administering a isolated cell comprising a nucleic acid sequence encoding VEGF operably linked to a constitutive promoter via any route or obtaining any effect as broadly encompassed by claim 14. 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.
Withdrawn rejection
The rejection regarding claims 9-13, 19, 20 has been withdrawn. The claims are drawn to an isolated mammalian cell comprising the vector of claim 1 wherein the vector is a lentiviral vector. While the cell must be transduced by a lentiviral particle, the cell contains the “lentiviral vector” of claim 1 once the contents of the lentiviral particle have entered the genome of the cell. Therefore, this language is acceptable.
Pending rejections
A) The specification does not enable a vector as broadly encompassed by claim 1 other than a composition comprising a lentiviral vector comprising a constitutive promoter, a nucleic acid encoding VEGF 165A isoform, and a WPRE enhancer. Claim 1 is drawn to a vector comprising: a polynucleotide comprising following operatively linked to each other: a constitutive promoter; a nucleic acid encoding a VEGF 165 isoform protein; and a WPRE enhancer comprising nucleotides 7564-8160 of SEQ ID NO: 23 or a functional complement thereof having at least 90% sequence identity to SEQ ID NO: 23.
The specification teaches a lentiviral vector comprising a constitutive promoter, a nucleic acid encoding a VEGF 165A isoform protein, and a WPRE enhancer (Examples). The specification teaches the term “lentiviral vector” refers exclusively to a viral particle capable of introducing exogenous nucleic acid into the cell (para 75-76). The specification conflates lentiviral plasmids and lentiviral vectors with lentiviral particles throughout the disclosure (para 77-78, 112) and discusses packaging systems for making viral particles (para 131-144). The specification does not correlate the lentiviral vector to any plasmid without lentiviral elements as broadly encompassed by claim 1. The specification does not correlate lentiviral vectors to any retroviral, AAV, adenoviral, baculoviral, etc. vector as broadly encompassed by claim 1. The specification does not correlate VEGF 165A isoform to VEGF 165B, VEGF 165C, or any other VEGF 165 isoform. The specification does not teach any WPRE enhancer “comprising nucleotides 7564-8160 of SEQ ID NO: 23 or a functional complement thereof having at least 90% sequence identity to SEQ ID NO: 23” as required in claim 1. The phrase does not make sense because “a functional complement thereof having at least 90% sequence identity to SEQ ID NO: 23” is broader than “nucleotides 7564-8160 of SEQ ID NO: 23” and has a different scope. The specification does not teach any “functional equivalents” of nucleotides 7564-8160 SEQ ID NO: 23. The specification does not teach any sequences with 90% identity to SEQ ID NO: 23 that are “functional equivalents”. The spec does not teach an assay for determining WPRE “functional equivalents” of SEQ ID NO: 23 or nucleotides 7564-8160 SEQ ID NO: 23. Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to make/use any vector as broadly encompassed by claim 1 other than a lentiviral vector comprising a constitutive promoter, a nucleic acid encoding VEGF 165A isoform, and a WPRE enhancer.
B) The specification does not enable claim 7 other than a viral packaging system comprising a lentiviral vector, a packaging plasmid, and an envelope plasmid. Claim 7 is drawn to a viral packaging system, but claim 1 does not require the vector is a viral vector. There is no way to package viral particles without the vector of claim 1 being a viral vector. The specification is limited to a lentiviral vector for reasons set forth above. Accordingly, the concept is not enabled other than when the system comprises a lentiviral vector.
C) The specification does not enable making/using any “biological equivalent thereof” of VEGF 165 as broadly encompassed by claim 13 other than VEGF 165A isoform. The specification does not correlate VEGF 165A isoform to VEGF 165B, VEGF 165C, or any other VEGF 165 isoform. The specification does not correlate The specification does not correlate VEGF 165A isoform to any “biological equivalent thereof”. Accordingly, the concept is not enabled other than VEGF 165A isoform.
D) The specification does not enable treating peripheral artery disease and/or critical limb ischemia in a mammal by administering an isolated mesenchymal comprising a lentiviral vector comprising a polynucleotide comprising a constitutive promoter, a nucleic acid encoding VEGF 165 isoform, and a WPRE enhancer operably linked to each other intravenously or intramuscularly as required in claim 14 other than direct injection into the diseased peripheral artery or the ischemic limb.
Claims 14-16 are summarized above.
The state of the art of VEGF gene therapy, transfecting bone marrow stem cells with a vector encoding VEGF165, bone marrow stem cell therapy for angiogenesis, and ex vivo VEGF gene therapy are discussed above.
The unpredictability of gene therapy is discussed above.
The teachings in the specification are discussed above.
Applicants have provided no greater assistance in methods of VEGF gene therapy than the art at the time of filing. In fact, it appears that the examples are all prophetic, thus requiring those of skill to rely on the art at the time of filing for enablement in view of the unpredictability of gene therapy using lentiviral vectors. The specification lacks written description for injecting the MSCs intravenously anywhere such that ischemia in a limb would be treated or be able to treat wound healing in the brain by crossing the blood brain barrier. The specification and the art at the time of filing do not teach that pancreatic, muscle, lung, skin, heart, reproductive, etc… cells containing the “vector” of claim 1 would treat the diseases listed other than marrow stromal cells. The specification fails to correlate the CMV promoter suggested to any other constitutive promoter, intravenous administration of genetically modified MSC (pg 69, line 3) to intramuscular injection such that the MSCs and exogenous VEGF expression would be targeted to cells of interest or that VEGF would be expressed to therapeutic levels in the desired tissue as broadly encompassed by claim 14-16. Given the unpredictability of the specific combination of target tissue, protein, promoter, route of administration and dosage required to obtain a therapeutic effect using gene therapy taken with the limited teachings in the specification, it would have required those of skill undue experimentation to determine how to express VEGF in isolated MSCs, using any constitutive promoter, or administering the MSCs intravenously or intramuscularly such that symptoms of peripheral artery disease or limb ischemia would be treated as broadly encompassed by claim 14-16 other than those methods known in the art at the time of filing.
Response to arguments
Applicants’ argument is noted but is not persuasive for reasons set forth above.
Indefiniteness
Claims 1-16, 18-20 remain and claim 21 is 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 metes and bounds of an WPRE enhancer “comprising nucleotides 7564-8160 of SEQ ID NO: 23 or a functional complement thereof having at least 90% sequence identity to SEQ ID NO: 23” in claim 1 cannot be determined. The phrase does not make sense because “a functional complement thereof having at least 90% sequence identity to SEQ ID NO: 23” is broader than “nucleotides 7564-8160 of SEQ ID NO: 23” and has a different scope. It is unclear whether the WPRE “functional equivalents” are of SEQ ID NO: 23 as a whole or just of nucleotides 7564-8160 SEQ ID NO: 23. Accordingly, those of skill would not be able to determine when they were infringing on the claim.
Response to arguments
Applicants’ argument is noted but is not persuasive for reasons set forth above.
Claim Rejections - 35 USC § 102
Claims 1-7, 21 as newly amended are rejected under pre-AIA 35 U.S.C. 102(e) as being anticipated by Zhong (EP 2623605).
Zhong taught an AAV packaging system (pg 7, para 43, 44, et al) comprising a nucleic acid sequence encoding VEGF (pg 10, para 65, pg 35, item 11; 39, claim 8) operably linked to a CMV, or EF1a promoter (pg 4, para 14) and a WPRE enhancer (pg 9, para 62; pg 34, item 8; pg 39, claim 7). The WPRE is a “functional equivalent” of SEQ ID NO: 23 as required in claim 1. This is equivalent to claim 1 and 21.
Zhong taught CMV, or EF1a promoter (pg 4, para 14) as required in claims 2-4.
The promoter is CMV as required in claim 5.
The WPRE is a “functional equivalent” of SEQ ID NO: 23 as required in claim 6
Zhong taught a packaging system comprising a vector, packaging helper plasmid, and an envelope plasmid as required in claim 7.
Zhong taught the vector was a lentiviral vector as required in claim 9.
Zhong taught the cells are hematopoietic cells (pg 23, par 171, et al.) which are marrow stromal cells as required in claim 11, 19.
The hematopoietic cells of Zhong inherently MUST express the marker pattern of claims 12 and 20 because they are marrow stromal cells.
Response to arguments
Applicants’ argument is noted but is not persuasive for reasons set forth above.
Claim Rejections - 35 USC § 103
Claim 8 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Zhong (EP 2623605) in view of FJ797421.1 (2009).
Zhong taught a plasmid encoding VEGF 165A isoform operably linked to a constitutive promoter and a WPRE as required in claim 1 for reasons set forth above.
Zhong did not teach the WPRE consisted of nucleotides 7564-8160 of the nucleic acid sequence of SEQ ID NO: 23 as required in claim 8.
However, the WPRE consisted of nucleotides 7564-8160 of the nucleic acid sequence of SEQ ID NO: 23 was well-known in the art as described by FJ797421.1.
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a plasmid encoding VEGF 165A isoform operably linked to a constitutive promoter and a WPRE as described by Zhong using the WPRE of FJ797421.1. Those of ordinary skill in the art at the time of filing would have been motivated to replace the WPRE of Zhong with the WPRE of FJ797421 as a matter of design choice. WPREs were interchangeable.
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
Claims 9-16, 18-20 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Zhong (EP 2623605) in view of Sun (Chinese Med. J., 2011, Vol. 124, No. 19, pg 3093-3097), Jiang (Journal of Shanghai Second Medical University, 2009, Vol. 21, No. 1, pg 12-18), and Jiang (Shanghai Jiaotong Saxue Xuebao, 2011, Vol. 31, No. 6, pg 753-758).
Zhong taught a viral vector encoding VEGF 165A isoform operably linked to a constitutive promoter and a WPRE as required in claim 1 for reasons set forth above.
Zhong did not teach the viral vector was a lentiviral vector as required in claim 9.
However, Sun taught a lentiviral vector encoding VEGF 165A (Methods).
Jiang (2009) taught transfecting MSCs with a lentiviral vector encoding VEGF 165:
PNG
media_image1.png
758
916
media_image1.png
Greyscale
Jiang (2011) also taught transfecting MSCs with a lentiviral vector encoding VEGF165:
PNG
media_image2.png
794
948
media_image2.png
Greyscale
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a plasmid encoding VEGF 165A isoform operably linked to a constitutive promoter and a WPRE as described by Zhong using a lentiviral vector described by Sun, Jiang (2009), and Jiang (2011). Those of ordinary skill in the art at the time of filing would have been motivated to replace the viral vector of Zhong with the lentiviral vector as a matter of design choice. Viral vectors were interchangeable.
Zhong did not teach transfecting MSCs as required in claim 10. However, Jiang (2009) and (2011) taught transfecting MSCs with a lentiviral vector encoding VEGF165. Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a plasmid encoding VEGF 165A isoform operably linked to a constitutive promoter and a WPRE as described by Zhong using a lentiviral vector to transduce MSCs as described Jiang (2009) and Jiang (2011). Those of ordinary skill in the art at the time of filing would have been motivated to replace the viral vector of Zhong with the lentiviral vector and transduce MSCs to treat bone regeneration as described by Jiang (2009) and Jiang (2011).
Zhong taught the cells are hematopoietic cells (pg 23, par 171, et al.) which are marrow stromal cells as required in claim 11, 19.
The hematopoietic cells of Zhong inherently MUST express the marker pattern of claims 12 and 20 because they are marrow stromal cells.
Claim 13 has been included because the cells must inherently express 5x10-6 ng of VEGF165A as evidenced by the therapeutic effect.
Zhong taught administering cells comprising the vector to treat disease, specifically ischemia (pg 36, items 29, 31; pg 39, claim 12; et al.) which is all that is required to meet the limitations of treating “critical limb ischemia” as required in claim 14-16. Injection may be intravenous or intramuscular or direct into an organ or tissue (para 21).
Injection may be direct into an organ or tissue (para 21) which is equivalent to claim 18.
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
Claims 1-7, 21 remain rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Chen (European J. Clin. Investigation, 2005, Vol. 35, pg 677-686) in view of Choi (Mol. Brain, 2014, Vol. 7, No. 7, pg 1-10).
Chen transfected CD34+ cord blood stem cells with an AAV vector encoding VEGF165 operably linked to a CMV promoter and LTR (pg 680, Fig. 1) and other elements for "high-level gene expression” in mammalian cells (pg 678, col. 2, 1st full paragraph) and administered the cells to mice intramyocardially to treat myocardial infarction (pg 679, 1st paragraph).
Chen used an LTR enhancer but did not teach using a WPRE enhancer as required in claim 9.
However, Choi optimized AAV for expression in cells using WPRE as required in claim 9.
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make stem cells comprising a sequence encoding VEGF operably linked to a CMV promoter and an enhancer as described by Chen using a WPRE enhancer as described by Choi. Those of ordinary skill in the art at the time of filing would have been motivated to enhance expression of VEGF.
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
Claim 8 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Chen (European J. Clin. Investigation, 2005, Vol. 35, pg 677-686) in view of Choi (Mol. Brain, 2014, Vol. 7, No. 7, pg 1-10) as applied to claims 1-7, 21 and further in view of FJ797421.1 (2009).
Chen and Choi taught a vector encoding VEGF 165A isoform operably linked to a constitutive promoter and a WPRE as required in claim 1 for reasons set forth above.
Chen and Choi did not teach the WPRE consisted of nucleotides 7564-8160 of the nucleic acid sequence of SEQ ID NO: 23 as required in claim 8.
However, the WPRE consisted of nucleotides 7564-8160 of the nucleic acid sequence of SEQ ID NO: 23 was well-known in the art as described by FJ797421.1.
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a vector encoding VEGF 165A isoform operably linked to a constitutive promoter and a WPRE as described by Chen and Choi using the WPRE of FJ797421.1. Those of ordinary skill in the art at the time of filing would have been motivated to replace the WPRE of Chen and Choi with the WPRE of FJ797421 as a matter of design choice. WPREs were interchangeable.
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
Response to arguments
Applicants arguments are noted but are not persuasive for reasons set forth above.
Double Patenting
Claims 1-16, 18-20 remain and claim 21 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10913957. Although the claims at issue are not identical, they are not patentably distinct from each other because claim 1 is identical to claim 4 of ‘957; claims 4-8 are identical to claims 7-11 of ‘957; claims 9-11 overlap with claims 12-14 of ‘957.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 9663564. Although the claims at issue are not identical, they are not patentably distinct from each other because claim 1 is identical to claim 5 of ‘564; claims 4-8 are identical to claims 8-11 of ‘564; claims 9-11 overlap with claims 12-14 of ‘564.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11939591. Although the claims at issue are not identical, they are not patentably distinct from each other because claim 1 is identical to claim 5 of ‘564; claims 4-8 are identical to claims 8-11 of ‘564; claims 9-11 overlap with claims 12-14 of ‘564.
Response to arguments
Rejections are not held in abeyance. Each rejection must be properly addressed with arguments or an amendment or a terminal disclaimer.
Claims 19 and 20 are objected to under 37 CFR 1.75 as being a substantial duplicate of claims 11 and 12. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Response to arguments
Applicants comment on this but the argument cannot be discerned. The scope is the same.
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.
Inquiry concerning this communication or earlier communications from the examiner should be directed to Michael C. Wilson who can normally be reached at the office on Monday through Friday from 9:30 am to 6:00 pm at 571-272-0738.
Patent applicants with problems or questions regarding electronic images that can be viewed in the Patent Application Information Retrieval system (PAIR) can now contact the USPTO’s Patent Electronic Business Center (Patent EBC) for assistance. Representatives are available to answer your questions daily from 6 am to midnight (EST). The toll free number is (866) 217-9197. When calling please have your application serial or patent number, the type of document you are having an image problem with, the number of pages and the specific nature of the problem. The Patent Electronic Business Center will notify applicants of the resolution of the problem within 5-7 business days. Applicants can also check PAIR to confirm that the problem has been corrected. The USPTO’s Patent Electronic Business Center is a complete service center supporting all patent business on the Internet. The USPTO’s PAIR system provides Internet-based access to patent application status and history information. It also enables applicants to view the scanned images of their own application file folder(s) as well as general patent information available to the public.
For all other customer support, please call the USPTO Call Center (UCC) at 800-786-9199.
If attempts to reach the examiner are unsuccessful, the examiner's supervisor, Tracy Vivlemore, can be reached on 571-272-2914.
The official fax number for this Group is (571) 273-8300.
Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638