DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment filed on 03/04/2026 has been entered.
Amended claims 1, 4-5, 17, 43, 116 and 118-119 are pending in the present application.
Applicant elected previously the following species: (a) fibroblasts as a species of cells; (b) RDEB (recessive dystrophic epidermolysis bullosa) as a species of C7-deficiency; and (c) injection as a species of administration.
Accordingly, amended claims 1, 4-5, 17, 43, 116 and 118-119 are examined on the merits herein with the above elected species.
Response to Amendment
The rejection under 35 U.S.C. 103 as being unpatentable over Georgiadis et al (J. Investigative Dermatology 136:284-292, published on line 09/22/2015; IDS) in view of Denaro et al (WO 2012/170911; IDS), Ishikawa et al (Nucleic Acids Research 20:4367, 1992), Bahnson et al (J. Virological Methods 54:131-143, 1995), and Fine et al (Journal of Hand Surgery 30B:1:14-22, 2005; IDS) was withdrawn in light of currently amended independent claims 1 and 43, particularly with the new limitation “b) the polynucleotide of SEQ ID NO: 34 encoding the functional C7”. Please note that the polynucleotide of SEQ ID NO: 34 is meant the entire polynucleotide sequence of SEQ ID NO: 34 (the 16,777-nucleotide sequence).
Claim Objections
Claims 1 and 43 are still objected to because of the misspelled term “psuedotyped”.
Claim Rejections - 35 USC § 112 (New Matter)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Amended claims 1, 4-5, 17, 43, 116 and 118-119 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 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. This is a new ground of rejection necessitated by Applicant’s amendment.
Amended independent claims 1 and 43 recite the limitation “b) the polynucleotide of SEQ ID NO: 34 encoding the functional C7”. The claims encompass a method for reducing symptoms associated with a type VII collagen (C7) deficiency or pseudosyndactyly in a patient in need thereof comprising the steps (i)-(iii) recited in currently amended independent claim 1 and 43, wherein the polynucleotide of SEQ ID NO: 34 (the 16,777-nucleotide sequence) encoding the functional C7. It is noted that the polynucleotide of SEQ ID NO: 34 is meant the entire SEQ ID NO: 34. The as-filed specification does not have a written support for this limitation.
As an initial matter, amended claims 1, 4-5, 17, 43, 116 and 118-119 have been introduced in the Amendment filed on 03/04/2026, so the claims themselves are not part of the original disclosure. 37 CFR § 1.115(a)(2). “New or amended claims which introduce elements or limitations that are not supported by the as-filed disclosure violate the written description requirement. . . . While there is no in haec verba requirement, newly added claims or claim limitations must be supported in the specification through express, implicit, or inherent disclosure. . . . The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed.” MPEP § 2163, part (I)(B); see also MPEP § 2163.02. In this case, the original specification does not convey the particular invention recited in claims 1, 4-5, 17, 43, 116 and 118-119 with reasonable clarity to skilled artisans. “The trouble is that there is no such disclosure, easy though it is to imagine it.” MPEP § 2163.05, part (II) (quoting In re Ruschig, 379 F.2d 990, 995, 154 USPQ 118, 123 (CCPA 1967)).
In the Amendment filed on 03/04/2026 (at page 6, first paragraph), once again Applicant cited paragraphs [007], [011], [025] and [0119] of the as-filed specification as an alleged written support for the above limitation. However, upon careful examination of these cited paragraphs it is noted that none of the cited paragraphs teach or suggest that the polynucleotide of SEQ ID NO: 34 (the 16,777-nucleotide sequence) encodes a functional type VII collagen (C7) as now encompassed broadly by currently amended claims. Once again, please note that the polynucleotide of SEQ ID NO: 34 is meant the entire SEQ ID NO: 34. Rather, the as-filed specification teaches specifically that SEQ ID NO: 34 is the sequence of the IGE308 plasmid, in which the sequence of nucleotides 3224-12058 is the collagen 7A1 open reading frame (ORF) encoding the human wild type collagen 7 protein (paragraphs [0201]-[0203]; Tables 9-10; and Figures 25A-25B). Accordingly, the as-filed specification does not have a written support for the limitation recited in currently amended claims.
The fact that the person of ordinary skill in the art could have carried out the claimed invention without undue experimentation based on applicants’ disclosure is inadequate to meet this requirement. “The Federal Circuit has pointed out that, under United States law, a description that merely renders a claimed invention obvious may not sufficiently describe the invention for the purposes of the written description requirement of 35 U.S.C. 112.” MPEP § 2163, part (I)(A).
Therefore, given the lack of sufficient guidance provided by the originally filed specification, it would appear that Applicants did not contemplate or have possession of invention as now claimed at the time the application was filed.
Claim Rejections - 35 USC § 112 (Lack of Written Description)
Amended claims 1, 4-5, 17, 43, 116 and 118-119 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 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. This is a modified rejection necessitated by Applicant’s amendment.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc). Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” Vas-Cath Inc. v. Mahurkar, 19USPQ2d at 1117. The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed. ”Vas-Cath Inc. v. Mahurkar, 19USPQ2d at 1116.
The instant claims encompass a method for reducing symptoms associated with a type VII collagen (C7) deficiency (e.g., recessive dystrophic epidermolysis bullosa as the elected species) or pseudosyndactyly (an inflammatory and fibrotic wound healing disorder in RDEB) in a patient in need thereof, the method comprising: (i) contacting fibroblasts obtained from the dermis of the C7-deficient patient with a VSV-G pseudotyped lentiviral vector particle comprising any polynucleotide of any length as long as it is a polynucleotide of SEQ ID NO: 34 (the 16,777-nucleotide sequence) and encodes a functional type VII collagen (C7) under any condition to form autologous genetically modified fibroblasts producing the functional C7, wherein the lentiviral vector particle has a transducing copy number in the range of 0.1 to about 5.0 copies per cell; preferably the genetically modified fibroblasts have an integrated transgene copy number of 0.41 to about 0.74 copy per cell; and wherein the VSV-G pseudotyped lentiviral vector particle is constructed from a transfer lentiviral vector comprising: (a) a modified 5’ long terminal repeat (LTR), wherein the promoter of the modified 5’ LTR is a cytomegalovirus promoter; (b) the polynucleotide of SEQ ID NO: 34 encoding the functional C7; (c) at least one lentiviral central polypurine tract (e.g., 2, 3, 4 or more at any locations); and (d) a modified 3’ LTR, wherein the modified 3’ LTR comprises any deletion or any size relative to the wild-type 3’ LTR; wherein a hepatitis virus post-transcriptional regulatory element (PRE) has been deleted; wherein the genetically modified fibroblasts have been transduced with any second VSV-G pseudotyped lentiviral vector; and wherein the genetically modified fibroblasts have been subjected to a spinoculation; (ii) culturing the autologous genetically modified fibroblasts to obtain an isolated population of C7-expressing genetically modified cells; and (iii) injecting directly to an affected site of the patient an effective amount of the genetically modified fibroblasts.
Apart from disclosing preparation of fibroblasts from a patient suffering recessive dystrophic epidermolysis bullosa (RDEB) that are transduced with the VSV-pseudotyped lentiviral vector (LV) designated INXN-2004 encoding a full-length wild-type human COL7A1 (the recombinant LV genome is derived from nucleotides 239-12,762 of the IGE308 plasmid with SEQ ID NO: 34, see Table 9 on pages 44-46) under specific optimized transduction conditions that include a combination of a first transduction with spinoculation together with a second transduction with spinoculation (super-transduction) and an intervening one cell passage for cells cultured on Retronectin (also known as recombinant human fibronectin fragment rFN-CH-296)-coated plates, that resulted in an integrated LV copy number of 0.41 or 0.74 per cell in the genetically modified fibroblasts for a Type VII collagen deficiency or pseudosyndactyly treatment (paragraphs [0137], [0205], [0295]-[0311], [0465], Tables 9, 31-32 and 46); the instant specification failed to describe a VSV-G pseudotyped lentiviral vector particle comprising any other polynucleotide of any length as long as it is a polynucleotide of SEQ ID NO: 34 (the 16,777-nucleotide sequence) and encodes a functional type VII collagen (C7) and wherein the lentiviral vector particle is constructed from a transfer lentiviral vector comprising the recited elements (a)-(d) and without a HPRE that results in the lentiviral vector particle having a transducing copy number in the range of 0.1 to about 5.0 copies per cell, particularly in the range of 0.41 to about 0.74 copy per cell, for autologous genetically modified C-7 deficient dermal fibroblasts as encompassed broadly by the instant claims. For example, apart from the recombinant LV genome comprised of the nucleotides 239-12,762 in SEQ ID NO: 34 (only nucleotides 3224-12058 of SEQ ID NO: 34 is the collagen 7A1 open reading frame (ORF) encoding the human wild type collagen 7 protein) which essential features or core elements do other VSV-G pseudotyped lentiviral vector particles possess such that they have a transducing copy number in the range of 0.1 to about 5.0 copies per cell for C-7 deficient, dermal fibroblasts under optimized transducing conditions, let alone under any other transducing conditions (e.g., transduction with any second VSV-G pseudotyped lentiviral vector and with a single spinoculation on any culture surface) as encompassed broadly by the instant claims? Apart from the nucleotides 3224-12058 of SEQ ID NO: 34 that encodes the human wild type collagen 7 protein, the instant specification fails to describe any other polynucleotide of SEQ ID NO: 34 of any size (e.g., 1 kb, 3 kb, 5 kb, 7 kb or more) that encodes a functional type VII collagen (C7). Which specific modifications (e.g., insertions, deletions, substitutions, or a combination thereof) should or should not be made in the nucleotides 3224-12058 of SEQ ID NO: 34 to generate any polynucleotide of SEQ ID NO: 34 of any size that still encodes a functional C7 as encompassed broadly by the instant claims?
It is noted that the LV designated INXN-2004 merely generated genetically modified fibroblasts having a vector copy number per cell in a range of 0.02 to 0.27 under single transduction conditions with or without spin transduction (see Table 31). Under the same optimized transduction conditions, the instant specification also disclosed that the LV vector designated INXN-2002 (containing a modified 5’ LTR with a CMV promoter, one lentiviral central polypurine tract element, a modified 3’UTR with a 400 bp-deletion, without a WPRE and also pseudotyped with a heterologous VSV-G envelope protein) merely generated 0.09 transducing vector copy number per cell while the LV vector designated INXN-2004 produced a transducing vector copy number of 0.41 and 0.74 per cell (paragraphs [0133], [0135]-[0137]; Figs. 13-14 and Table 46); and this disclosure indicates or suggests at least that structural components of a VSV-G pseudotyped lentiviral vector also play an important and direct role in determining an integrated transgene copy number per cell in transducing fibroblasts. There is no evidence of record indicating that the LV designated INXN-2004 is capable of forming genetically modified, dermis-derived, C-7 deficient fibroblasts with an integrated transgene copy number in excess of 0.74 per cell (e.g., 1.0, 2.0, 3.0, 4.0 or about 5.0 per cell) under any transducing conditions, let alone a VSV-G pseudotyped lentiviral vector particle comprising a polynucleotide of SEQ ID NO: 34 of any size as long as it encodes a functional C7. Please note that the physiological art is recognized as unpredictable (MPEP 2164.03).
Since the prior art before the effective filing date of the present application (03/18/2016) failed to provide sufficient guidance and/or written description for the above issues as evidenced at least by the teachings of Chen et al (Nature Genetics 32:670-675, 2002; IDS), Woodley et al (J. Invest. Dermatol. 121:1021-1028, 2003; IDS), Marinkovich et al (Poster presented at the American Society of Human Genetics Annual Meeting, Baltimore, Maryland, October 8, 2015; IDS), Georgiadis et al (J. Investigative Dermatology 136:284-292, published on line 09/22/2015; IDS), and Siprashvilli et al (US 2019/0382724, paragraph [0114]); it is incumbent upon the instant specification to do so. Furthermore, the instant specification also fails to provide and describe at least a representative number of species for a broad genus of a VSV-G pseudotyped lentiviral vector particle comprising any polynucleotide of any length as long as it is a polynucleotide of SEQ ID NO: 34 (the 16,777-nucleotide sequence) that encodes a functional type VII collagen (C7) and is derived from a lentiviral transfer vector comprising the recited elements (a)-(d) along with the lack of a HPRE element, wherein said lentiviral vector particle has a transducing copy number in the range of 0.1 to about 5.0 copies per cell for C7-deficient dermal fibroblasts, for use in the treatment methods as claimed broadly.
The claimed invention as a whole is not adequately described if the claims require essential or critical elements which are not adequately described in the specification and which are not conventional in the art as of Applicants’ 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. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641, 1646 (1998). The skilled artisan cannot envision at least a representative number of species for a broad genus of a VSV-G pseudotyped lentiviral vector particle comprising any polynucleotide of any length as long as it is a polynucleotide of SEQ ID NO: 34 (the 16,777-nucleotide sequence) that encodes a functional type VII collagen (C7) and is derived from a lentiviral transfer vector comprising the recited elements (a)-(d) along with the lack of a HPRE element, wherein said lentiviral vector particle has a transducing copy number in the range of 0.1 to about 5.0 copies per cell for C7-deficient dermal fibroblasts, for use in the treatment methods as claimed broadly; and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method. 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 Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481, 1483.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Response to Arguments
Applicant’s arguments related to the above modified 112(a) rejection in the Amendment dated 03/04/2026 (pages 6-7) have been fully considered but they are respectfully not found persuasive for the reasons discussed below.
Applicant argued simply that solely to advance prosecution of the application, independent claims 1 and 43 have been amended to indicated that the VSV-G pseudotyped lentiviral vector particle comprising a polynucleotide of SEQ ID NO: 34. Applicant also reiterated that the paragraphs [0007], [0011] and [0119] provide ample support for currently amended claims.
First, please refer to the above modified rejection for details, and note that the above modified rejection is not a New Matter rejection.
Second, under the same optimized transduction conditions that include a combination of a first transduction with spinoculation together with a second transduction with spinoculation (super-transduction) and an intervening one cell passage for cells cultured on Retronectin (also known as recombinant human fibronectin fragment rFN-CH-296)-coated plates, the instant specification simply disclosed that the LV vector designated INXN-2002 (containing a modified 5’ LTR with a CMV promoter, one lentiviral central polypurine tract element, a modified 3’UTR with a 400 bp-deletion, without a WPRE and also pseudotyped with a heterologous VSV-G envelope protein) merely generated 0.09 transducing vector copy number per cell while the LV vector designated INXN-2004 (the recombinant LV genome is derived from nucleotides 239-12,762 of the IGE308 plasmid with SEQ ID NO: 34, see Table 9 on pages 44-46) produced a transducing vector copy number of 0.41 and 0.74 per cell (paragraphs [0133], [0135]-[0137]; Figs. 13-14 and Table 46).
Third, apart from the nucleotides 3224-12058 of SEQ ID NO: 34 that encodes the human wild type collagen 7 protein, the instant specification fails to describe any other polynucleotide of SEQ ID NO: 34 of any size (e.g., 1 kb, 3 kb, 5 kb, 7 kb or more) that encodes a functional type VII collagen (C7). Which specific modifications (e.g., insertions, deletions, substitutions, or a combination thereof) should or should not be made in the nucleotides 3224-12058 of SEQ ID NO: 34 to generate any polynucleotide of SEQ ID NO: 34 of any size that still encodes a functional C7 as encompassed broadly by the instant claims?
Claim Rejections - 35 USC § 112 (Scope of Enablement)
Amended claims 1, 4-5, 17, 43, 116 and 118-119 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 reducing symptoms associated with a type VII collagen (C7) deficiency or pseudosyndactyly in a patient in need thereof, the method comprising:
(i) transducing fibroblasts obtained from the patient’s dermis with a VSV-G pseudotyped lentiviral vector comprising the sequence of nucleotides 239-12,762 in SEQ ID NO: 34 and encoding COL7A1 with spinoculation on a culture surface coated with rFN-CH-296; thereby forming autologous genetically modified fibroblasts having an integrated transgene copy number in the range of 0.1 to 0.27 copy per cell;
(ii) performing one cell passage after the first transduction step (i) followed by transducing fibroblasts with the VSV-G pseudotyped lentiviral vector with spinoculation for a second time on a culture surface coated with rFN-CH-296 to form autologous genetically modified fibroblasts having an integrated transgene copy number in the range of 0.40 to 0.74 copy per cell;
(iii) culturing the autologous genetically modified fibroblasts after step (ii); and
(iv) injecting directly to an affected site of the patient an effective amount of the genetically modified fibroblasts;
does not reasonably provide enablement for other method for reducing symptoms in a patient suffering from a type VII collagen deficiency or pseudosyndactyly as claimed broadly. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims. This is a modified rejection necessitated by Applicant’s amendment.
The factors to be considered in the determination of an enabling disclosure have been summarized as the quantity of experimentation necessary, the amount of direction or guidance presented, the state of the prior art, the relative skill of those in the art, the predictability or unpredictability of the art and the breadth of the claims. Ex parte Forman, (230 USPQ 546 (Bd Pat. Appl & Unt, 1986); In re Wands, 858 F.2d 731, 8 USPQ 2d 1400 (Fed. Cir. 1988)).
The instant specification is not enabled for the instant broadly claimed invention for the reasons discussed below.
1. The breadth of the claims
The instant claims encompass a method for reducing symptoms associated with a type VII collagen (C7) deficiency (e.g., recessive dystrophic epidermolysis bullosa as the elected species) or pseudosyndactyly (an inflammatory and fibrotic wound healing disorder in RDEB) in a patient in need thereof, the method comprising: (i) contacting fibroblasts obtained from the dermis of the C7-deficient patient under any condition with a VSV-G pseudotyped lentiviral vector particle comprising any polynucleotide of any length as long as it is a polynucleotide of SEQ ID NO: 34 (the 16,777-nucleotide sequence) that encodes a functional type VII collagen (C7) to form autologous genetically modified fibroblasts producing the functional C7, wherein the lentiviral vector particle has a transducing copy number in the range of 0.1 to about 5.0 copies per cell; preferably the genetically modified fibroblasts have an integrated transgene copy number of 0.41 to about 0.74 copy per cell; and wherein the VSV-G pseudotyped lentiviral vector particle is constructed from a transfer lentiviral vector comprising: (a) a modified 5’ long terminal repeat (LTR), wherein the promoter of the modified 5’ LTR is a cytomegalovirus promoter; (b) the polynucleotide sequence encoding the functional C7; (c) at least one lentiviral central polypurine tract (e.g., 2, 3, 4 or more at any locations); and (d) a modified 3’ LTR, wherein the modified 3’ LTR comprises any deletion or any size relative to the wild-type 3’ LTR; wherein a hepatitis virus post-transcriptional regulatory element (PRE) has been deleted; wherein the genetically modified fibroblasts have been transduced with any second VSV-G pseudotyped lentiviral vector; and wherein the genetically modified fibroblasts have been subjected to a spinoculation (e.g., including a single spinoculation); (ii) culturing the autologous genetically modified fibroblasts to obtain an isolated population of C7-expressing genetically modified cells; and (iii) injecting directly to an affected site of the patient an effective amount of the genetically modified fibroblasts. It is noted that the term “patient” in the present application refers to a mammal (paragraph [085]).
2. The state and the unpredictability of the prior art
Before the effective filing date of the present application (03/18/2016), little was known about the use of an effective amount of autologous genetically modified, C7-deficient dermal fibroblasts transduced with a VSV-G pseudotyped lentiviral vector particle comprising a polynucleotide of SEQ ID NO: 34 encoding a functional type VII collagen (C7) and is constructed from a transfer lentiviral vector comprising the elements a)-d) and lacks of a HPRE as recited in independent claims 1 and 43, wherein the lentiviral vector particle has a transducing copy number in the range of 0.1 to about 5.0 copies per cell, for treating a patient suffering from a type VII collagen deficiency (e.g., recessive dystrophic epidermolysis bullosa) or pseudosyndactyly as evidenced at least by the teachings of Fine et al (Journal of Hand Surgery 30B:1:14-22, 2005; IDS), Chen et al (Nature Genetics 32:670-675, 2002; IDS), Woodley et al (J. Invest. Dermatol. 121:1021-1028, 2003; IDS), Marinkovich et al (Poster presented at the American Society of Human Genetics Annual Meeting, Baltimore, Maryland, October 8, 2015; IDS), Georgiadis et al (J. Investigative Dermatology 136:284-292, published on line 09/22/2015; IDS), and Siprashvilli et al (US 2019/0382724, paragraph [0114]).
3. The amount of direction or guidance provided
Apart from disclosing preparation of fibroblasts from a patient suffering recessive dystrophic epidermolysis bullosa (RDEB) that are transduced with the VSV-pseudotyped lentiviral vector (LV) designated INXN-2004 encoding a full-length wild-type human COL7A1 (the recombinant LV genome is derived from nucleotides 239-12,762 of the IGE308 plasmid with SEQ ID NO: 34, see Table 9 on pages 44-46) under specific optimized transduction conditions that include a combination of a first transduction with spinoculation together with a second transduction with spinoculation (super-transduction) and an intervening one cell passage for cells cultured on Retronectin (also known as recombinant human fibronectin fragment rFN-CH-296)-coated plates, that resulted in an integrated LV copy number of 0.41 or 0.74 per cell in the genetically modified fibroblasts for a Type VII collagen deficiency or pseudosyndactyly treatment (paragraphs [0137], [0205], [0295]-[0311], [0465], Tables 9, 31-32 and 46); the instant specification failed to provide sufficient guidance for an ordinary skilled artisan on how to make and use any other VSV-G pseudotyped lentiviral vector particle comprising any polynucleotide of SEQ ID NO: 34 of any length as long as it encodes a functional C7 and wherein the lentiviral vector particle is constructed from a transfer lentiviral vector comprising the recited elements (a)-(d) and without a HPRE that results in the lentiviral vector particle having a transducing copy number in the range of 0.1 to about 5.0 copies per cell, particularly in the range of 0.41 to about 0.74 copy per cell, for autologous genetically modified C-7 deficient dermal fibroblasts under any transduction conditions (e.g., without subjecting the fibroblasts to first spinoculation on a culture surface coated with rFN-CH-296 and a second spinoculation) for treating a patient suffering from a C7 deficiency or pseudosyndactyly in the treatment methods as claimed broadly. Lee et al (Biologicals 37:203-209, 2009) already taught that retronectin enhances lentivirus-mediated gene delivery into hematopoietic progenitor cells by promoting colocalization of lentivirus and target cells (see Abstract). Even with the same VSV-G pseudotyped LV designated INXN-2004, it failed to mediate a transducing vector copy number in the range of 0.41 to about 0.74 copy per cell under single transduction conditions with or without spin transduction (with a vector copy number per cell ranging from 0.02 to 0.27; see Table 31), let alone a transducing vector copy number in excess of 0.74 per cell (e.g., 0.75, 1.0, 2.0, 3.0, 4.0 or about 5.0 copies per cell). The only other disclosed VSV-G pseudotyped LV designated INXN-2002 (containing a modified 5’ LTR with a CMV promoter, one lentiviral central polypurine tract element, a modified 3’UTR with a 400 bp-deletion, without a WPRE or HPRE and also pseudotyped with a heterologous VSV-G envelope protein) does not have a transducing vector copy number in the range of 0.4 to 0.74 copy per cell under all transduction conditions tested for C7-deficient dermal fibroblasts, including under the optimized transduction conditions comprising the combination of first transduction with spinoculation together with a second transduction with spinoculation (super-transduction), in which the INXN-2002 LV vector merely generated 0.09 transducing vector copy number per cell (paragraphs [0133], [0135]-[0137], [0463]-[0464]; Figs. 13-14 and Table 46). This disclosure indicates or suggests at least that structural components of a VSV-G pseudotyped lentiviral vector also play an important and direct role in determining an integrated transgene copy number per cell in transducing C7-deficient dermal fibroblasts.
Accordingly, which specific modifications (e.g., substitution(s), insertion(s), deletion(s), or a combination thereof) along the length of the nucleotide sequence of SEQ ID NO: 34 (the 16,777-nucleotide sequence from which the VSV-pseudotyped lentiviral vector designated INXN-2004 encoding a full-length wild-type human COL7A1 is derived) should or should not be made such that the generated VSV-G pseudotyped lentiviral vector particle comprising a polynucleotide of SEQ ID NO: 34 at any size that encodes a functional C7 is still able to have a transducing copy number in the range of 0.1 to about 5.0 copies per cell for the autologous genetically modified, C7-deficient dermal fibroblasts; particularly an integrated transgene copy number in excess of 0.74 copy per cell (e.g., 1, 2, 3, 4 or 5 copies per cell) even under the disclosed optimized transduction conditions, let alone under any transduction conditions as encompassed broadly by the instant claims? Which specific coding sequence(s) for the COL7A1 is superfluous/deleted in SEQ ID NO: 34, such that the resulting VSV-G pseudotyped lentiviral vector particle comprising any polynucleotide of SEQ ID NO: 34 of any size (e.g., 1 kb, 3 kb, 5 kb, 7 kb or more) and encoding a functional C7 that still endows the injected genetically modified, autologous C7-deficient dermal fibroblasts the ability to yield the desired therapeutic effects? The specification stated “Results from continuing development indicated that deletion of the RRE element and the use of a large 400 bp deletion in the 3’LTR U3 region in the pSMPUW vector construct, combined with the requirement to package a large COL7A1 gene (8.8 kbp), resulted in a negative impact on LV-COL7 vector production (infectious tier) and subsequent transduction and C7 protein expression in RDEB fibroblast cells” (paragraph [0185]). Additionally, Chang et al (Molecular Therapy 9(Suppl_1): S29-S30, Abstract 72, 2004; IDS) also disclosed that the central polypurine tract (cPPT) plays an important role in increasing lentivirus-mediated gene transfer efficiency, and the effectiveness of cPPT in the infectivity of lentiviral particles critically depends on the position and the number of cPPT incorporated in the vector. Thus, it is unpredictable and there are many factors involved in the transduction/spinoculation conditions, along with the number and position/orientation of various essential structural elements present in a transducing lentiviral vector particle that determine formation of genetically modified fibroblasts having an integrated transgene copy number in the range of 0.1 to about 5.00 copies per cell, particularly any integrated transgene copy number in excess of 0.74 copy per cell, as required by the instant treatment method claims for reducing symptoms associated with type VII collagen deficiency or pseudosyndactyly in a patient. There is no evidence of record indicating that the LV designated INXN-2004 is capable of forming genetically modified fibroblasts with an integrated transgene copy number in excess of 0.74 per cell under any transducing conditions; and any functional VSV-G pseudotyped lentiviral vector particle comprising a polynucleotide encoding a functional C7 with the polynucleotide of SEQ ID NO: 34 that includes the plasmid backbone comprising the Ampicillin resistance gene operably linked to a promoter, let alone for such VSV-G pseudotyped lentiviral vector comprising such polynucleotide mediates the desired integrated transgene copy number per cell in genetically modified C7-deficient dermal fibroblasts as broadly claimed.
Since the prior art before the effective filing date of the present application failed to provide sufficient guidance regarding to the aforementioned issues, it is incumbent upon the present application to do so. Given the state of the prior art, coupled with the lack of sufficient guidance provided by the present application, it would have required undue experimentation for a skilled artisan to make and use the instant invention as claimed broadly.
The physiological art is already recognized as unpredictable (MPEP 2164.03). As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112, first paragraph requires:
That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; in cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws; in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.
Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maizel.).
Accordingly, due to the lack of sufficient guidance provided by the specification regarding to the issues set forth above, the state and unpredictability of the relevant art, and the breadth of the instant claims, it would have required undue experimentation for one skilled in the art to make and use the instant broadly claimed invention.
Response to Arguments
Applicant’s arguments related to the above modified 112(a) rejection in the Amendment dated 03/04/2026 (pages 7-8) have been fully considered but they are respectfully not found persuasive for the reasons discussed below.
Once again, Applicant argued basically that solely to advance prosecution of the present application, claims 1 and 43 have been amended essentially to the Office’s statement on the enabled scope of Applicant’s specification, specifically the claims have been amended to recite “the VSV-G pseudotyped lentiviral vector particle comprising a polynucleotide of SDQ ID NO: 34 encoding a functional C7”. Applicant argued that one skilled in the art would readily recognize that as long as the C7 is functional, the claimed methods would function properly. Once again, Applicant argued that Applicant’s application amply shows that use of spin transduction (spinoculation) resulted in copy numbers in the range of 0.1 to 5.0 copies without undue burden; and the methods do not need to include “spinoculation on a culture surface coated with rFN-CH-296”, which is a preferred step, for Applicant’s claimed methods to work properly. Applicant also argued that the Office provides no evidence to dispute this. Applicant further argued that Applicant’s claimed methods work properly when a transducing copy number is in the range of 0.1 to about 5.0 copies per cell, and there is no reason to believe that one skilled in the art would be required to perform undue experimentation to make and use the claimed subject matter.
First, please refer to the above modified enablement rejection for more details, particularly the Wands factor analysis on why it would have required undue experimentation for one skilled in the art to make and use treatment methods of currently amended independent claims 1 and 43.
Second, it is not the simple matter that any VSV-G pseudotyped lentiviral particle comprising a polynucleotide of SEQ ID NO: 34 of any size (e.g., 1 kb, 3 kb, 5 kb, 7 kb or more) that encodes a functional C7 and said lentiviral particle is constructed from a transfer lentiviral vector comprising the elements a)-d) along with a deleted HPRE as recited in currently amended independent claim 1 or 43, and is capable of having a transducing copy number of any value within the recited range of 0.1 to about 5.0 copies per cell, particularly any value within the range of 0.41 to about 0.74 copy per cell, for autologous genetically modified C7-deficient dermal fibroblasts under any condition. Instead, the main issue is the unpredictability and the involvement of many factors in the transduction/spinoculation conditions (or contacting), along with the number and position/orientation of various essential structural elements present in a transducing lentiviral vector particle comprising a polynucleotide of SEQ ID NO: 34 encoding a functional C7 that determine the formation of genetically modified fibroblasts having an integrated transgene copy number in the range of 0.1 to about 5.00 copies per cell, including any integrated transgene copy number within the range of 0.41 to about 0.74 copy per cell, as required by the instantly claimed treatment methods for reducing symptoms associated with type VII collagen deficiency or pseudosyndactyly in a patient.
Third, please note that the disclosed VSV-G pseudotyped LV designated INXN-2002 (containing a modified 5’ LTR with a CMV promoter, one lentiviral central polypurine tract element, a modified 3’UTR with a 400 bp-deletion, without a WPRE and also pseudotyped with a heterologous VSV-G envelope protein) does not have a transducing vector copy number in the range of 0.4 to 0.74 copy per cell for C7-deficient dermal fibroblasts under all transduction conditions tested, including under the optimized transduction conditions comprising the combination of first transduction with spinoculation together with a second transduction with spinoculation (super-transduction), in which the INXN-2002 LV vector merely generated 0.09 transducing vector copy number per cell (paragraphs [0133], [0135]-[0137], [0463]-[0464]; Figs. 13-14 and Table 46). Additionally, there is no evidence of record indicating that the LV designated INXN-2004 is capable of forming genetically modified fibroblasts with an integrated transgene copy number in excess of 0.74 per cell under any transducing conditions; and any functional VSV-G pseudotyped lentiviral vector or a polynucleotide sequence encoding a functional C7 comprising the entire nucleic acid sequence of SEQ ID NO: 34 that includes the plasmid backbone comprising the Ampicillin resistance gene operably linked to a promoter, let alone for such VSV-G pseudotyped lentiviral vector particle comprising such polynucleotide sequence mediates the desired integrated transgene copy number per cell in the genetically modified fibroblasts as broadly claimed.
Fourth, with respect to the issue that the claimed methods would work without requiring coating the culture surface with rFN-CH-296 (Retronectin) please note that Lee et al (Biologicals 37:203-209, 2009) already taught that retronectin enhances lentivirus-mediated gene delivery into hematopoietic progenitor cells by promoting colocalization of lentivirus and target cells. Thus, without coating the culture surface with rFN-CH-296 that enhances lentivirus-mediated gene delivery would the desired integrated transgene copy number at least in the range of 0.1 to 0.27 copy per cell be achieved via a single spinoculation as encompassed by the instant claims? Applicant also acknowledged that rFN-CH-296 enhances the efficiency of lentiviral- and retroviral-mediated gene transduction. It is noted that all experiments in the as-filed specification were conducted with spinoculation on a culture surface coated with rFN-CH-296 (Retronectin).
Accordingly, due to the lack of sufficient guidance provided by the specification regarding to the issues set forth in the above modified 112(a) rejection above, the state and unpredictability of the relevant art, and the breadth of the instant claims, it would have required undue experimentation for one skilled in the art to make and use the instant broadly claimed invention.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Amended claims 1, 4-5, 17, 43, 116 and 118-119 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. This is a modified rejection necessitated by Applicant’s amendment.
In both amended independent claims 1 and 43, it is unclear what is encompassed by the limitation “wherein the genetically modified fibroblasts have been transduced with a second VSV-G pseudotyped lentiviral vector”. This is because it is unclear whether the second VSV-G pseudoyped lentiviral vector is the same or different from the first VSV-G pseudotyped lentiviral vector particle. Additionally, it is also unclear what is encompassed by the limitation “wherein the genetically modified fibroblasts have been subjected to a spinoculation”. It is unclear whether the genetically modified fibroblasts have been subjected to a spinoculation once or twice. Clarification is requested because the metes and bounds of the claims are not clearly determined. Moreover, it is also unclear what is encompassed by the limitation “the polynucleotide of SEQ ID NO: 34 encoding the functional C7” recited in element b) of currently amended independent claims 1 and 43. This is because the polynucleotide of SEQ ID NO: 34 means the entire polynucleotide sequence of SEQ ID NO: 34, and yet in step (i) both claims also recite the limitation “a polynucleotide of SEQ ID NO: 34 encoding a functional C7”. A polynucleotide of SEQ ID NO: 34 normally refers to any polynucleotide of any length as long it is a polynucleotide of SEQ ID NO: 34. Thus, it is unclear exactly what Applicant intend to claim. Clarification is requested because the metes and bounds of the claims are not clearly determined.
Conclusions
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Quang Nguyen, Ph.D., at (571) 272-0776.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s SPE, James Douglas (Doug) Schultz, Ph.D., may be reached at (571) 272-0763.
To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Group Art Unit 1631; Central Fax No. (571) 273-8300.
Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to (571) 272-0547.
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/QUANG NGUYEN/
Primary Examiner, Art Unit 1631
Prosecution Insights