DETAILED ACTION
The present application is being examined under the pre-AIA first to invent provisions.
Applicant’s preliminary amendments to the claims filed on February 27, 2025 have been received and entered. Claims 1-67 have been canceled, while claim 68-97 are newly added. Claims 68-97 are pending in the instant application.
Priority
Instant application is a continuation of application no 17/153,636 filed on 01/20/2021, which is continuation of application no 15820212 filed on 11/21/2017, which is a divisional of application no 14687556, filed on 04/15/2015, which is divisional of application no 12/024454, filed on 02/01/2008, which claims priority to provisional applications 60/888,067, filed February 2, 2007 and 60/888,305, filed February 5, 2007.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/12/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claims 68-97 are under consideration.
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.
Claims 68-96 and 87 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 for inhibiting rejection of a vascularized tissue or vascularized organ transplant or inhibiting arteriosclerosis in a human allograft transplant recipient, the method comprising: intraportally or directly administering to the human allograft transplant recipient a composition comprising an adenoviral vector comprising a nucleic acid encoding an endothelial growth factor-3 inhibitor to produce an effective amount of the endothelial growth factor inhibitor-3 that inhibit transplant rejection or inhibit arteriosclerosis, wherein the nucleic acid is expressible in cells of the human allograft transplant recipient or expressible in the cells of transplanted tissue,
wherein the endothelial growth factor inhibitor comprises a soluble human VEGFR-3 polypeptide;
wherein the soluble VEGFR-3 polypeptide comprises the amino acids 47-314 of SEQ ID NO: 6 (that includes the first, second, and third immunoglobulin-like domains of human VEGFR-3) that binds VEGF-C or VEGF-D and inhibits stimulation of human VEGFR-3 by VEGF-C or inhibits stimulation of human VEGFR-3 by VEGF-D and an immunoglobulin constant domain fused to the soluble human VEGFR-3 polypeptide and wherein the vascularized tissue or vascularized organ transplant is a heart or kidney allograft,
does not reasonably provide enablement for using any other nucleic acid that comprises any nucleotide sequence that encodes an endothelial growth factor inhibitor comprising any soluble human VEGFR-3 polypeptide inhibitor that inhibits stimulation of human VEGFR-3 by VEGF-C inhibits stimulation of human VEGFR-3 by VEGF-D, using nucleotide sequence that encodes an amino acid sequence at least 95% identical to amino acids 47-224 of SEQ ID NO: 6, at least 95% identical to amino acids 47-314 of SEQ ID NO: 6 or at least 95% identical to amino acids 24-775 of SEQ ID NO: 6 or fragments thereof that bind VEGF-C. 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 use the invention commensurate in scope with these claims.
In determining whether Applicant’s claims are enabled, it must be found that one of skill in the art at the time of invention by applicant would not have had to perform “undue experimentation” to make and/or use the invention claimed. Such a determination is not a simple factual consideration, but is a conclusion reached by weighing at least eight factors as set forth in In re Wands, 858 F.2d at 737, 8 USPQ 1400, 2d at 1404. Such factors are: (1) The breadth of the claims; (2) The nature of the invention; (3) The state of the art; (4) The level of one of ordinary skill in the art; (5) The level of predictability in the art; (6) The amount of direction and guidance provided by Applicant; (7) The existence of working examples; and (8) The quantity of experimentation needed to make and/or use the invention.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
Nature of the Invention:
Claims are directed to a method for inhibiting rejection of a vascularized tissue or vascularized organ transplant, or for inhibiting arteriosclerosis in a human allograft transplant recipient, comprising: administering to a human allograft transplant recipient a composition that comprises a nucleic acid that comprises any nucleotide sequence that encodes any endothelial growth factor inhibitor, wherein the nucleic acid is expressible in cells of the human allograft transplant recipient or expressible in cells of the transplanted tissue or organ to produce an amount of the endothelial growth factor inhibitor effective to inhibit rejection or inhibit arteriosclerosis, wherein the endothelial growth factor inhibitor comprises a soluble human VEGFR-3 polypeptide that inhibits stimulation of human VEGFR-3 by VEGF-C or inhibits stimulation of human VEGFR-3 by VEGF-D (claim 68), herein the encoded soluble VEGFR-3 polypeptide comprises the VEGFR-3 extracellular domain, or a fragment thereof sufficient to bind VEGF-C or VEGF-D, and wherein the fragment includes amino acids 138 - 226 of SEQ ID NO: 6 (claim 80), wherein the endothelial growth factor inhibitor comprises any amino acid sequence at least 95% identical to amino acids 138-226 of SEQ ID NO: 6, that binds VEGF- C or VEGF-D (claim 94) or wherein the nucleic acid comprises a nucleotide sequence that encodes an amino acid sequence at least 95% identical to amino acids 47-224 of SEQ ID NO: 6, at least 95% identical to amino acids 47-314 of SEQ ID NO: 6 or at least 95% identical to amino acids 24-775 of SEQ ID NO: 6 or fragments thereof that bind VEGF-C (claim 95). Claims further embrace administering at least one growth factor inhibitor selected from the group consisting of: inhibitors of VEGFR-1; inhibitors of VEGFR-2; inhibitors of PDGFR-alpha; and inhibitors of PDGFR-beta (84).
Breadth of the claims
It is noted that instant rejection is based on four separate issues:
absence of an enabling disclosure of delivering any nucleic acid encoding endothelial growth factor inhibitor comprising any other soluble human VEGFR-3 polypeptide that binds VEGF-C or VEGF-D and inhibits stimulation of human VEGFR-3 by VEGF-C in any predictable animal model to establish any reasonable correlation of inhibiting rejection of vascularized tissue or vascularized organ as embraced by the breadth of the claims;
the absence of an enabling disclosure of delivering and expressing in cells plurality of different nucleic acid fragments or variants encoding any soluble human VEGFR-3 polypeptide that inhibits stimulation of human VEGFR-3 by VEGF-C to produce an effective amount of endothelial growth factor inhibitor effective to inhibit plurality of different vascularized tissue or organ rejection as embraced by the breadth of the claims.
The deficiencies were identified by the Office after analysis of the disclosure provided in the instant application. Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404. The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
Guidance of the Specification and The Existence of Working Examples:
The specification teaches a method inhibiting the rejection of a cardiac allograft (transplants from a donor organism to a genetically non-identical organism of the same species) in rat and mouse perfused with adeno-virally expressed soluble VEGFR-3 receptor extracellular domainVEGFR-3-Ig that traps VEGFR-3 ligands, see para. [00378], VEGFR-3 neutralizing monoclonal antibody that decreases inflammation and inflammation-driven arteriosclerosis in chronically rejecting mouse cardiac allografts, see para. [371 375 of the published application] The specification teaches intraportally with adenovirus vector encoding the soluble form of VEGFR-3 (Ad.VEGFR-3-Ig, VEGF-C/D-trap) that inhibited VEGF-3 resulting in improved cardiac allograft survival (see example 7). . In view of general teaching in the specification, for purposes of the rejection, the common themes of all these in vivo methods is the ability to target and express nucleic acid encoding a polypeptide comprising any soluble human VEGFR-3 polypeptide that inhibits stimulation of human VEGFR-3 by VEGF-C, whether locally or within a cell which the nucleic acid transforms. However, considering the wide range of nucleic acid fragments or variants encoding any soluble human VEGFR-3 polypeptide that inhibits stimulation of human VEGFR-3 by VEGF-C encompassed, and wide range of methods of administration, along with the inhibiting rejection of plurality of different organ allograft, and given that Applicant has not provided specific guidance and direction that would overcome lack of reasonable predictability in a predictable animal model and the state of the art, the Artisan would have to perform undue experimentation to reasonably predict working embodiment encompassed by Applicant’s claims commensurate with full scope of the claims.
The relative skill of those in the art:
The relative skill of those in the art is high.
State of the Art and Predictability of the Art and the Amount of Experimentation
Necessary:
The invention is in the nature of the specific targeting of cell populations to affect localized binding and expression of therapeutic genes, and the transformation of tissues with genes, to effect gene therapy. Therefore, an in- depth analysis of gene itself will suffice to review the nature of the invention, as the same requirements to effect gene therapy are also part of the other methods. Specifically, as will be shown below, the ability to target, binding, express enough mRNA and protein therefrom, for a long enough time to affect such therapy is required of these inventions. The claims recite use of a composition comprising any nucleic acid that comprises any nucleotide sequence that encodes an endothelial growth factor inhibitor comprising any soluble human VEGFR-3 polypeptide that inhibits stimulation of human VEGFR-3 by VEGF-C or inhibits stimulation of human VEGFR-3 by VEGF-D. The guidance provided in the specification is limited to a nucleic acid encoding soluble VEGFR-3 receptor extracellular domain-Ig that traps VEGFR-3 ligands, see para. [371]. The claim as presented read on fragment and/or variant of nucleic acid encoding a endothelial growth factor inhibitor comprising any soluble human VEGFR-3 polypeptide. Claim 94 is directed to an endothelial growth factor inhibitor comprising any amino acid sequence at least 95% identical to amino acids 138-226 of SEQ ID NO: 6, that binds VEGF- C or VEGF-D (claim 94) or a fragment comprising amino acids 138 - 226 of SEQ ID NO: 6 (claim 80). Claims further embrace any vector that is induced by an endogenous stress in the organ transplant recipient such as an elevation of a biological marker correlated with rejection (claims 70-71). The specification discloses that the fragment minimally comprises enough of the VEGFR-3 sequence to bind the ligand, and may comprise the complete receptor, or extracellular domain fragments or a polypeptide have an amino acid sequence at least 95% identical to a ligand binding fragment thereof. It is noted that specification further contemplates that the genus of similar polypeptides can alternatively be defined by the ability of encoding polynucleotides to hybridize to the complement of a nucleotide sequence that corresponds to the cDNA sequence encoding the R-3 receptor (see para. 131-134 of the published application). The specification discloses using constructs that includes Fc domain human IgG fragments fused to the C-terminus of the receptor fragments comprising extracellular domain (ECD) that was sufficient for ligand binding (example 1). It is further disclosed that a series of R-3 constructs with C-termini between Ig domains 2 and 3 of VEGFR-3 (R-3 C through F constructs) was created by PCR using the expression plasmid comprising the R-3 D1-3 transcript as template, T7 as forward primer and a reverse primer (see para 379, table 2). It is generally known that PCR amplification can result in mutations (Rychlik et al. Nuc. Acids Res. 18:6409-6412, 1990, IDS). The specification does not indicate that any nucleic acids that both hybridize to the complement of nucleotide sequence encoding the amino acid set forth in SEQ ID NO: 6 that traps VEGFR-3 ligands capability under highly stringent conditions, nor does specification disclose placing any sequence to a public depository. It is noted that polynucleotides to hybridize to the complement of a nucleotide sequence that corresponds to the cDNA sequence encoding the R-3 receptor is embraced by the genus. However, specification fails to disclose a sequence of 50 to100 base pairs encoding SEQ ID: 6 or a fragment thereof that would hybridize with the target sequence, and if it does not contain the essential motifs that are required for contemplated biological activity, such a sequence will hybridize to plurality of sequence embraced by the soluble VEGFR-3 gene, but will not be functional and show contemplated biological activity.
The guidance provided in the specification is limited to inhibiting the rejection of a cardiac allograft (transplants from a donor organism to a genetically non-identical organism of the same species) in rat and mouse perfused with adenoviral expressed soluble VEGFR-3 receptor extracellular domainVEGFR-3-Ig that traps VEGFR-3 ligands. The specification teaches identification of Ig-domains of a particular receptor ECD. "D 1-3" refers to a construct containing at least the first three lg-domains, and intervening sequence between domains 1 and 2 and 2 and 3, of a particular construct. Table 2 defines the boundaries of the lg-domains for VEGFR-3 of the invention. These boundaries are significant as the boundaries chosen can be used to form constructs, and so can influence the binding properties of the resulting constructs (see para. 83, table 2). It is disclosed that ECD of VEGFR-3 (R-3) has six intact Ig-like domains--D5 of R-3 is cleaved post-translationally into disulfide linked subunits leaving VEGFR-3. In general, receptor fragments of at least the first three lg-domains for this family are sufficient to bind ligand (see para. 84 page 20 of the specification) (emphasis added). Thus, the claimed genus must necessarily include structures of nucleotide encoding amino acid set forth in SEQ ID NO: 6 that includes at least the first three lg-domains for this family are sufficient to bind ligand. It is further disclosed that the sequence intermediate in between second and third Ig domain of R-3 is important for ligand binding (see para. 385 of the published application, example 1). It is further noted that fragment consisting of residue 138-329 of SEQ ID NO:6 is unable to bind with VEGF-C (see table 4) (emphasis added). Hence, the nature of the invention is not reasonably predictable for any of the numerous numbers of possible coding sequences claimed, due to the unpredictability of structure-function relationships. Moreover, given the lack of reasonable predictability between structure and function, the identification and subsequent analysis for using a fragment or variant of soluble VEGFR-3 of each variant, would require further and undue experimentation without reasonable expectation of success. It is noted that the unpredictability of a particular art area may alone provide reasonable doubt as to the accuracy of the broad statement made in support of enablement of claims. See Ex parte Singh, 17 USPQ2d 1714 (BPAI 1991). It is also well established in case law that the specification must teach those of skill in the art how to make and how to use the invention as broadly claimed. In re Goodman, 29 USPQ2d at 2013 (Fed. Cir. 1994), citing In re Vaeck, 20 USPQ2d at 1445 (Fed. Cir. 1991).
In summary, the claims of the instant application are drawn to a broad genus of sequences that are not apparent from the disclosure of the invention. In view of the lack of teachings or guidance provided by the specification with regard to enabled, encompassing an enormous number of sequence variants that may be derived from SEQ ID NO: 6, described supra, the lack of teachings or guidance provided by the specification to overcome the art-recognized unpredictability and difficulty inherent in isolation of said sequences and subsequent testing for inhibiting rejection of organ allograft, and for the specific reasons cited above, it would have required undue experimentation for an Artisan of skill to make and use the claimed invention. Hence, absent a strong showing by Applicant, in the way of specific guidance and direction, and/or working examples demonstrating the same, such invention as claimed by Applicant is not enabled. The task may require even further experimentation due to the lack of predictability between sequence structure and biological function desired. This would require a significant degree of inventive effort, with each of the many intervening steps, upon effective reduction to practice, not providing any guarantee of success in the succeeding steps.
Claim Rejections - 35 USC § 112-written description
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 68-96 and 97 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 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The independent claims and dependent claims therefrom are directed to a method of inhibiting rejection of a tissue or vascularized organ transplant, or for inhibiting arteriosclerosis in a human allograft transplant recipient, comprising: administering to a human allograft transplant recipient a composition that comprises a nucleic acid that comprises any nucleotide sequence that encodes an endothelial growth factor inhibitor, wherein the endothelial growth factor inhibitor comprises any soluble human VEGFR-3 polypeptide that inhibits stimulation of human VEGFR-3 by VEGF-C or inhibits stimulation of human VEGFR-3 by VEGF-D (claim 68), subsequently limiting to the polypeptide comprises the VEGFR-3 extracellular domain, or a fragment thereof sufficient to bind VEGF-C or VEGF-D, and wherein the fragment includes amino acids 138 - 226 of SEQ ID NO: 6. or wherein the endothelial growth factor inhibitor comprises any amino acid sequence at least 95% identical to amino acids 138-226 of SEQ ID NO: 6, that binds VEGF- C or VEGF-D (claim 94). Dependent claim limits the nucleic acid comprises a nucleotide sequence that encodes an amino acid sequence at least 95% identical to amino acids 47-224 of SEQ ID NO: 6, at least 95% identical to amino acids 47-314 of SEQ ID NO: 6 or at least 95% identical to amino acids 24-775 of SEQ ID NO: 6 or fragments thereof that bind VEGF-C (claim 95). Claims further embrace any vector that is induced by an endogenous stress in the organ transplant recipient such as an elevation of a biological marker correlated with rejection (claims 7-8).
Thus, the genus comprises use of a composition comprising any nucleic acid that comprises any nucleotide sequence that encodes an endothelial growth factor inhibitor comprising any soluble human VEGFR-3 polypeptide that inhibits stimulation of human VEGFR-3 by VEGF-C or inhibits stimulation of human VEGFR-3 by VEGF-D. The claims further embrace a regulatory sequence that is induced by any endogenous stress in the organ transplant recipient comprising an elevation of any biological marker correlated with rejection.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
The specification teaches cardiac allograft (transplants from a donor organism to a genetically non-identical organism of the same species) in rat and mouse perfused with adenovirally expressed soluble VEGFR-3 receptor extracellular domainVEGFR-3-Ig that traps VEGFR-3 ligands, see para. [00378], VEGFR-3 neutralizing monoclonal antibody that decreases inflammation and inflammation-driven arteriosclerosis in chronically rejecting mouse cardiac allografts, see para. [00439].
The specification contemplates that the binding unit comprises a polypeptide similar or identical in amino acid sequence to a VEGFR-3 polypeptide or fragment thereof, preferably from the same species as the targeted growth factor(s). Thus, for binding to human growth factors, a binding unit preferably comprises a polypeptide that comprises an amino acid similar or identical to a fragment of SEQ ID NO: 6, where the fragment and the polypeptide binds one or more growth factors selected from the group consisting of VEGF-C and VEGF-D. The fragment minimally comprises enough of the VEGFR-3 sequence to bind the ligand, and may comprise the complete receptor, or extracellular domain fragments or polypeptides have an amino acid sequence at least 80% identical to a ligand binding fragment thereof. Fragments that are more similar, e.g., 85% - 100% are highly preferred. It is noted that specification further contemplates that the genus of similar polypeptides can alternatively be defined by the ability of encoding polynucleotides to hybridize to the complement of a nucleotide sequence that corresponds to the cDNA sequence encoding the R-3 receptor (see para. 95-96 of the specification). The specification discloses using constructs that includes Fc domain human IgG fragments fused to the C-terminus of the receptor fragments comprising extracellular domain (ECD) that was sufficient for ligand binding (example 1). It is further disclosed that a series of R-3 constructs with C-termini between Ig domains 2 and 3 of VEGFR-3 (R-3 C through F constructs) was created by PCR using the expression plasmid comprising the R-3 D1-3 transcript as template, T7 as forward primer and a reverse primer (see para 379, table 2). It is relevant to note that it is generally known that PCR amplification can result in mutations (Rychlik et al. Nuc. Acids Res. 18:6409-6412, 1990). The specification does not indicate that any nucleic acids that both hybridize to the complement of nucleotide sequence encoding the amino acid set forth in SEQ ID NO: 6 that traps VEGFR-3 ligands capability under highly stringent conditions, nor does specification disclose placing any sequence to a public depository. It is noted that polynucleotides to hybridize to the complement of a nucleotide sequence that corresponds to the cDNA sequence encoding the R-3 receptor is embraced by the genus. However, specification fails to disclose a sequence of 50 to100 base pairs encoding SEQ ID: 6 or a fragment thereof that would hybridize with the target sequence, however if it does not contain the essential motifs that are required for contemplated biological activity, such a sequence will hybridize to plurality of sequence embraced by the soluble VEGFR-3 gene, but will not be functional and show contemplated biological activity. It is emphasized that hybridization under highly stringent conditions requires a high degree of structural complementarity, nucleic acids that hybridize to the complement of nucleotide sequence encoding the amino acid set forth in SEQ ID NO: 6 must share many nucleotides in common with nucleotide encoding SEQ ID NO: 6. Thus, the claimed genus necessarily includes partial structures of nucleotide encoding amino acid set forth in SEQ ID NO: 6. The disclosure of nucleotide sequence combined with the knowledge in the art regarding hybridization may even put one in possession of the genus of nucleic acids that would hybridize under stringent conditions to nucleotide sequence encoding SEQ ID NO: 6. However, without a recognized correlation between structure and function, those of ordinary skill in the art would not be able to identify without further testing which of those nucleic acids that hybridize to nucleotide sequence encoding amino acid set forth in SEQ ID NO: 6 that would show contemplated biological activity in plurality of organ or tissue allograft. Thus, those of ordinary skill in the art would not consider the applicant to have been in possession of the claimed genus of nucleic acid based on the single species disclosed in example 1.
It is further noted that specification describes that invention may contain conservative substitutions of one or more amino acids in the amino acid sequence represented by SEQ ID NO:6 or substitutions, insertions or deletions of non-essential amino acids (see para 157 of the specification). Accordingly, a non-essential amino acid is a residue that may be altered in the amino acid sequences shown in SEQ ID NO: 6 without substantially altering the biological function. The specification does not provide guidance to one of skill in art to structurally predict or recognize plurality of different structures of mutants or variants of any nucleic acid that comprises any soluble human VEGFR-3 polypeptide showing contemplated biological activity. It is emphasized that biological activity of a protein is highly dependent on the overall structure of the protein itself and the primary amino acid sequence determines the conformation of the protein (Skolnick et al. (TIBTECH 18:34-39, 2000). Thus, it is apparent that a minor structural difference in factor could result in substantially different activities. The specification does not teach any sequence other than SEQ ID NO: 6 or a nucleic acid encoding SEQ ID NO: 6 that would also show contemplated biological activity. The specification does not provide any disclosure as to what would have been the required structure for other fragments and variants of nucleic acid encoding SEQ ID: 6. As such, the Artisan of skill could not predict that Applicant possessed any species, except for the nucleic acid encoding SEQ ID NO: 6 that could be used for inhibiting rejection of a cardiac allograft. There is no evidence on record that sequence that any nucleotide sequence that encodes an endothelial growth factor inhibitor comprising any soluble human VEGFR-3 polypeptide that inhibits stimulation of human VEGFR-3 by VEGF-C or inhibits stimulation of human VEGFR-3 by VEGF-D as broadly claimed would have contemplated biological activity. Hence, only the nucleotide sequence encoding VEGFR-3 consisting of amino acid sequence of SEQ ID NO: 6 or soluble VEGFR-3 polypeptide comprises the amino acids 47-314 of SEQ ID NO: 6 (that includes the first, second, and third immunoglobulin-like domains of human VEGFR-3)could be demonstrated as possessed for inhibiting allograft.
The DNA sequence of genus of regulatory sequence that is induced by any endogenous stress in the organ transplant recipient comprising an elevation of any biological marker correlated with rejection have not been disclosed. Based upon the prior art there is expected to be sequence variation among the species of DNA sequences that is induced by any endogenous stress in the organ transplant recipient comprising an elevation of any biological marker correlated with rejection. The specification has provided a general description of such as a sequence. The specification however has not disclosed the sequences of any of the regulatory sequence that is induced by any endogenous stress in the organ transplant recipient comprising an elevation of any biological marker correlated with rejection as embraced by the claims. There is no evidence on the record of a relationship between the structures of the DNA molecules of any of the embraced regulatory sequence that is induced by any endogenous stress in the organ transplant recipient comprising an elevation of any biological marker correlated with rejection would provide any reliable information about the structure of DNA molecules within the genus. There is no evidence on the record that embraced sequences had known structural relationships to each other; the art indicated that there is variation between DNA sequences of various inducible promoter or signal sequences.
The claimed invention as a whole is not adequately described if the claims require essential or critical elements or motifs which are not adequately described in the specification and which is not conventional in the art as of applicants effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. In the instant case, the claimed embodiments of genus of regulatory sequence that is induced by any endogenous stress in the organ transplant recipient comprising an elevation of any biological marker correlated with rejection lack a written description. The specification fails to describe what DNA molecules fall into this genus. The skilled artisan cannot envision the detailed chemical structure of the encompassed sequence that is induced by any endogenous stress in the organ transplant recipient comprising an elevation of any biological marker correlated with rejection sequences, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation.
The skilled artisan cannot envision the detailed chemical structure of the sequence of any variants showing contemplated biological activity, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) and Amgen lnc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
In conclusion, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that Applicant is in possession of using any nucleic acid encoding the endothelial growth factor inhibitor comprising any soluble human VEGFR-3 polypeptide that inhibits stimulation of human VEGFR-3 by VEGF-C or inhibits stimulation of human VEGFR-3 by VEGF-D or any sequence that is induced by any endogenous stress in the organ transplant recipient comprising an elevation of any biological marker correlated with rejection as embraced by the breadth of the claims and that retain the biological activity to inhibit rejection of a vascularized tissue or vascularized organ transplant, or for inhibiting arteriosclerosis at the time the application was filed. Thus, it is concluded that the written description requirement is not satisfied for the claimed genus.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 68-69, 72-83, 85-86, 94-96 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over DeVries et al (USPGPUB 20030180294, dated 09/25/2003), Kerjaschki et al (J Am Soc Nephrol 15: 603–612, 2004, IDS), Alitalo et al (WO02/060950, dated 08/08/2002, IDS) and Harding et al (USPGPUB 20060110364, dated 05/25/2006)
With respect to claims 68, 73-74 and 94, DeVries teaches a method for inhibiting graft rejection such as corneal transplantation in patient by administering to the graft recipient (mammalian patient) an effective amount of a pharmaceutical composition comprising an anti-VEGFR-3 antibody or a composition comprising an adenoviral vector (see para. 101, 104) comprising a nucleic acid that comprises a nucleotide sequence that encodes an endothelial growth factor inhibitor before transplantation of the tissue into the recipient such as nucleic acid molecule encoding soluble VEGFR-3 receptor (see paragraph 37), that inhibits endothelial growth factor such as VEGF-C from binding to its receptor thereby inhibits graft related lymphangiogenesis in the cornea of the patient (see entire document, abstract, page 6, paragraph [0051] through [0053], [0047], claims 1-38 of the publication, in particular). The patient or recipient is a human patient (see paragraph [0025), wherein the graft is a xenograft or allograft (see paragraph [22). DeVries teaches that the composition is administered topically, local injection or systemically, or by intravenous injection, (see paragraphs 17, 97-98). DeVries teaches that the composition is administered topically, local injection or systemically by extended-release method, or by intravenous injection, subcutaneous injection, or intraperitoneal injection (see paragraphs 17, 97-98).
With respect to claim 75, 77, DeVries teaches administering to the patient prior to transplantation an effective amount of a pharmaceutical composition containing a VEGFR-3 inhibitor (see para. 16). The term perioperatively is interpreted as around the operation that could be prior, during or following the transplant procedure and therefore DeVries disclosure of administering the composition to the patient prior to transplantation is interpreted as perioperative administration.
Regarding claim 76, DeVries teaches administration is repeated over a period of at least one month or over a period of at least six months (see para. 15).
With respect to claims 77-79, 96, DeVries teaches detecting an elevated risk of allograft rejection or a patient exhibiting one or more symptoms consistent with allograft rejection to administer the composition (see para. 82). DeVries discloses that the pharmaceutical composition is administered to the recipient over a period of at least 30 days or at least six months which encompassed the claimed term of at least 1-90 days or 1-60 or 1-15 days before or subsequent to corneal transplantation (see claims 28-32 of the application, paragraphs 85-87).
With respect to claims 85-86, DeVries teaches a method further comprises administering to the recipient a composition comprising an immunosuppressive agent such as prednisolone acetate, corticosteroids, cyclosporine (antibiotic), tacrolimus (FK506), antibody to T lymphocytes such as anti-T lymphocyte (known in the art as OKT3), anti-CD4+ cells (see paragraphs [0082] through [0084).
DeVries differ from claimed invention by not disclosing (i) transplant is a vascularized tissue transplant such as kidney (ii) nucleic acid further comprises at least one expression control sequence operatively connected to the sequence that encodes the endothelial growth factor inhibitor, (ii) administering nucleic acid as part of viral vector (iii) wherein the encoded soluble VEGFR-3 polypeptide comprises the VEGFR-3 extracellular domain, or a fragment thereof sufficient to bind VEGF-C or VEGF-D, and wherein the fragment includes amino acids 24-775 of SEQ ID NO: 6 or fragment thereof (68, 80-83, 94-95).
Regarding claim 72, Kerjaschki et al teach human kidney, a vascularized organ transplant rejection is associated with significant de novo formation of lymphatic vessels in transplant and apparently involved active tubulointerstital infiltration of macrophage that produce VEGF-C and VEGF-D, (abstract, page 608-609). It is further disclosed that inflammation-associated with de novo lymphangiogenesis may involve macrophage infiltrates into the lymphatic endothelia in addition to CD4+ and CD8+ T cells (alloimmunity response) (see page 603). Kerjaschki et al teach that VEGFR-3 is also expressed in lymphatic endothelial cells of newly formed blood vessels (see para bridging pages 609-610). These lymphatic neoangiogenesis not only contributes to export of rejection infiltrate but also is involved in the maintenance of alloreactive immune response in renal transplant and thus could provide a novel therapeutic target (pages 610 to 611). Kerjaschki et al differs from claimed invention by not disclosing soluble VEGFR-3.
However, Alitalo teaches various soluble VEGFR-3 that can block the interaction between VEGF-C and VEGFR-3/Flt4(see pages 97-98). It is further disclosed that VEGF-C induced lymphangiogenesis is inhibited by soluble VEGFR-3 (see pages 102, 109). Exemplary soluble VEGFR-3/Flt4 that inhibits the activity of VEGF-C and VEGF-D include VEGFR-3-Ig, which is the extracellular ligand binding domain of human VEGFR-3 fused to human Igl Fe domain, (see pages 104-105 and 114).
Claims 68, 80-83, 94 and 95 are included as the reference soluble VEGFR-3 polypeptide comprises the extracellular ligand binding domain of human VEGFR-3 fused to human Ig Fe domain, see pages 104-105 and 114. Claim 83 is included as the Alitalo teaches the first three Ig-homology domain of human VEGFR-3 and IgG Fe domain is used to generate soluble VEGFR-3 and the VEGFR-3-Ig bound VEGF-C and VEGF-D (see page 108). It is noted that claims are included as the term "comprising" is open-ended. It expands to first and second lg-like domains of VEGFR-3 to include the third lg-like domain or the extracellular domain of VEGFR-3. Alitalo teaches VEGFR-3 polypeptide comprises the amino acid sequence 100% identical to the claimed SEQ ID NO: 6, which comprises the claimed residues 138-226, 47-224, 47-314 and 24-775 as claimed.
The combination of references differs from claimed invention by not disclosing nucleic acid further comprises at least one expression control sequence operatively connected to the sequence that encodes the endothelial growth factor inhibitor, (ii) administering nucleic acid as part of adenoviral vector.
Harding et al teach a viral vector-mediated delivery and expression of polynucleotides encoding soluble sVEGFR-3 for use in the inhibition of lymphangiogenesis (see para. 3). It is further disclosed that the vector comprises the coding sequence for a soluble form of VEGFR3 operably linked to a promoter, wherein viral vector is an AAV (see para. 10). Harding et al teach an adenoviral vector which encodes sVEGFR3 (rAAV-VEGFR-3Fc), encompassing the 1-3 Ig-like domains of human VEGFR-3 gene fused to the human IgG1 heavy chain (Fc) cloned downstream of the constitutive CMV (see para. 132).
With respect to claim 69, Harding further teaches employing an inducible promoter such as Tet to achieve controlled expression (see para. 1100). Harding teaches a method of inhibiting one or more of lymphangiogenesis and expressing sVEGFR3, in a mammalian subject, comprising: administering a replication-deficient vector of the invention to a mammalian subject in need of treatment to inhibit one or more of lymphangiogenesis (see claim 19).
Therefore, it would have been obvious to one of ordinary skill in the art at the time the invention was made to modify the method as disclosed in DeVries of administering to the graft recipient an effective amount of a nucleic acid that comprising a nucleotide sequence that encodes a soluble VEGFR-3 receptor(see paragraph 37) , wherein said nucleic acid is incorporated in an adeno viral vector as disclosed in Harding prior to organ (kidney) transplantation to a recipient as disclosed in Kerjaschki et al, to inhibits endothelial growth factor such as VEGF-C from binding to its receptor thereby inhibiting graft related lymphangiogenesis in the transplant tissue of the patient, as instantly claimed, with a reasonable expectation of success, at the time of filing of instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to do so because Kejaschki teaches that lymphatic angiogenesis in human kidney transplant rejection is mediated by VEGF-C and VEGF-D and potential targets for inhibition would lead inhibition in transplant rejection in kidney (supra). Claim 32 is included in this rejection because it would have been obvious to one of ordinary skill in the art to screen and/or follow up the organ transplant recipient for any symptoms of an acute rejection reaction and then administer the composition to the recipient upon detection of symptoms of acute rejection. One of skill in the art would have been expected to have a reasonable expectation of success because prior art teaches successful use of soluble VEGFR-3/Flt4 that could be used to block interaction between VEGF-C and its receptors and thereby VEGF-C induced lymphangiogenesis (see page 98, lines 1-2, page 102) . It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (www .uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
Thus, the claimed invention, as a whole, is clearly prima facie obvious in the absence of evidence to the contrary.
Claims 87-93 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over DeVries et al (USPGPUB 20030180294, dated 09/25/2003), Kerjaschki et al (J Am Soc Nephrol 15: 603–612, 2004), Alitalo et al (WO02/060950, dated 08/08/2002) and Harding et al (USPGPUB 20060110364, dated 05/25/2006) as applied above for claim 68 and 94 and further in view of Briscoe (WO2005/041877, dated 5/12/2005)/ Richards (US20050222066, dated 10/6/2005).
The combined teaching of teachings of DeVries, Kerjaschki, Alitalo and Harding et al have been described above and relied in same manner here. The combination of references fails to teach the step of further comprises administering to a donor a composition, prior to harvesting a vascularized organ for transplantation into the recipient, prior to harvesting the organ for transplantation into the recipient and that the vascularized organ could be tissue transplant.
Briscoe teaches a method of inducing tolerance or inhibiting rejection of vascularized organ, i.e., cardiac (heart) allograft (see page 7, para. 29) by administering to a donor, a composition comprising an effective amount of an endothelial growth factor VEGF antagonist before the organ is harvested for transplant (see entire document, abstract, page 11, para. 38) into the recipient for inhibiting graft rejection (see page 3, para. 11, page 18, para. 60, page 9, para. 33). The reference VEGF antagonist includes humanized antibody, chimeric, monoclonal, polyclonal, anti-idiotic antibodies and binding fragment thereof that binds to VEGF (see paragraphs 23, 14) and/or anti-VEGF receptor-2 (KDR) antibody (see paragraph 18, 63). The reference recipient is a human or animal (See page 18, para. 60). The reference composition is administered by any suitable route such as orally, intravenously, intramuscularly or intraperitoneally (see page 19, para. 66). The reference VEGF antagonist can be administered to the recipient before, concurrently or after immunosuppressive agent (see page 18, para. 61). The composition is administered locally or systemically (see page 19, para.66). The composition is administered at different time and more than once (see page 18, para.61). The skilled artisan will be able to determine the appropriate timing for administration of various antagonists (see page 18, para.61-62). The immunosuppressive agent comprises at least one corticosteroid such as prednisone, dexamethasone, methylprednisolone or prednisolone (see page 18, paragraph 0058, in particular), calcineurine inhibitor such as cyclosporine A, FK506, anti-proliferative agent such as IL-2 signal transduction inhibitor, monoclonal or polyclonal anti-lymphocyte antibodies such as OKT3, antifungal agent such as rapamycin or mycophenolic acid (see page 18, para.58). The method further comprises administering to the donor a nucleic acid that encodes an endothelial growth factor inhibitor (see page 4, para.13).
Likewise, Richards teaches a method of inhibiting transplantation rejection (e.g., prevention of allograft rejection or liver (which is a vascularized organ or organ fragment capable of performing functions of the organ or capable of regenerating into liver) transplant by modulating the expression of a VEGF and/or VEGFR gene in a tissue explant (e.g., a liver transplant, see para. [0152] to [0154])) comprising: (a) synthesizing a siNA molecule of the invention, which can be chemically-modified, wherein the NA comprises a single stranded sequence having complementarity to RNA of the VEGF and/or VEGFR gene; and (b) contacting a cell of the tissue explant, i.e., liver derived from a particular subject (donor) or organism with the siNA molecule under conditions suitable to modulate (e.g., inhibit) the expression of the VEGF and/or VEGFR gene in the tissue explant and then introducing the tissue explant back into the subject (recipient) or organism the tissue was derived from (donor) or into another subject (recipient) or organism under conditions suitable to modulate (e.g., inhibit) the expression of the VEGF and/or VEGFR gene in that subject or organism (see para. 152-154]). Those skilled in the art will recognize that other drug compounds and therapies can similarly be readily combined with the nucleic acid molecules of the instant invention ( para 675). Claim 14 is included as Richards also teach tissue transplant (see para. [145-147).
Therefore, it would have been obvious to one of ordinary skill in the art at the time the invention was made to modify the teachings of prior art of administering to the graft recipient an effective amount of a nucleic acid that comprising a nucleotide sequence that encodes a soluble VEGFR-3 receptor(see paragraph 37) by including the step of administering to an organ donor a composition comprising an endothelial growth factor inhibitor that binds to VEGF prior to harvesting the organ and then transplant the organ into the recipient as taught by the Briscoe/ Richards. One having ordinary skill in the art would have been motivated with expectation of success to do so because blocking VEGFR-3 mediated lymphangiogenesis and growth factors mediated angiogenesis in organ donor is expected to further lower or minimize the risk of graft rejection and to improve the odds of tolerance in the recipient. Since blocking VEGFR-3 interacting with its ligands VEGF-D and VEGF-C is desirable and has been predictable at the time the invention was made to inhibit cardiac allograft rejection and arteriosclerosis, there would have been reasonable expectation of success in combine the references teachings to arrive at the claimed invention. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (www.uspto.gov/web/offices/dcom/bpai /prec/fd071925 .pdf).
Thus, the claimed invention, as a whole, is clearly prima facie obvious in the absence of evidence to the contrary.
Claims 84, 97 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over DeVries et al (USPGPUB 20030180294, dated 09/25/2003), Kerjaschki et al (J Am Soc Nephrol 15: 603–612, 2004), Alitalo et al (WO02/060950, dated 08/08/2002) and Harding et al (USPGPUB 20060110364, dated 05/25/2006) as applied above for claims 69 and 94 and further in view of Hirst et al (USP 6,921,763 , 07/26/2005).
The teaching of DeVries, Kerjaschki, Alitalo and Harding have been described above and relied in same manner here. The combination of reference differs from claimed invention by not disclosing inhibiting rejection of a vascularized tissue or solid organ by administering to the recipient a composition that comprises at least one growth factor inhibitor selected from the group consisting of inhibitor ofVEGFR-1, VEGFR-2, VEGFR-3.
Hirst teaches a method for inhibiting graft rejection or transplant rejection or chronic occlusive pulmonary disease (arteriosclerosis) by administering to the graft recipient an effective amount of a pharmaceutical composition comprising a vascular endothelial growth factor inhibitor such as tyrosine kinase inhibitor pyraxopyrimidine which inhibits stimulation of its receptor such as VEGFR-3 (see claims 39, 48, 49, in particular).
Therefore, it would have been obvious to one of ordinary skill in the art at the time the invention was made to modify the method of prior art by including the pharmaceutical composition comprising a vascular endothelial growth factor inhibitor such as tyrosine kinase inhibitor pyraxopyrimidine in combination with which inhibits stimulation of its receptor such as VEGFR-3 useful for inhibiting rejection of a vascularized tissue or solid organ as taught by the Hirst with the graft expressing sVEGFR3 that is useful for inhibiting graft rejection as claimed in the instant application, with a reasonable expectation of success, at the time of filing of instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One having ordinary skill in the art would have been motivated to combine known substance with another known substance useful for the same purpose because the application nucleic acid encoding sVEGFR-3 overexpression is useful in a method for inhibiting graft rejection such as corneal transplantation or kidney transplantation in human patient (solid organ) by inhibiting graft rejection and graft related lymphangiogenesis in the cornea of the patient (supra). Hirst teaches the advantage of tyrosine kinase inhibitor pyraxopyrimidine is that it inhibits one or more VEGF-A, VEGF-B, VEGF-C or VEGF-D that stimulate its receptor such as VEGFR-3 and is useful for inhibiting graft or transplant rejection or chronic occlusive pulmonary disease (arteriosclerosis) (see claims 39, 48, 49). Since inhibiting VEGF ligand interaction with its receptor VEGFR2 and/or VEGFR3 is desirable and has been predictable at the time the invention was made to inhibit organ/graft rejection, there would have been reasonable expectation of success in combine the references teachings to arrive at the claimed invention. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (www .uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
Thus, the claimed invention, as a whole, is clearly prima facie obvious in the absence of evidence to the contrary.
Conclusion
No claims allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Geissler et al (European Journal of Cardio-thoracic Surgery 29 (2006) 767—771, IDS) teaches patients with only moderate rejection during the first 12 months (ISHLT < IIIa) had a significantly higher density of VEGFR-3 at 0.5 month in comparison to patients with at least one episode of clinically relevant rejection.
Sho et al (Transplantation 80(6): 717-722, Sept 2005) teaches Sho et al teach a method for inducing tolerance or inhibiting cardiac allograft rejection of a vascularized organ such as cardiac graft (aka heart transplant, which is a vascularized tissue) or inhibiting arteriosclerosis by administering to a mammalian transplant recipient, i.e., mice a composition that comprises an endothelial growth factor inhibitors such as neutralizing monoclonal antibodies against VEGFR-1 and VEGFR-2 that block the respective ligand VEGF and VEGF-C from binding to the VEGFR-1 and VEGFR-2 ( Figure 3).
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/ANOOP K SINGH/Primary Examiner, Art Unit 1632
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