DETAILED ACTION
Claims 1-21 are currently pending.
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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 8/29/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 7, 10 and 20 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.
Claim 7, which depends from claim 6, recites the limitation “wherein said cap genes and rep gene are also under control of the second inducible regulatory element”, and renders claim 7 indefinite since it is unclear if the claim means the cap genes and rep gene are part of the second module comprising AAV helper genes, and which claim 1 indicates is under control of the second inducible regulatory element.
Regarding claim 10 and the limitation “...wherein the second regulatory element activates expression of said cap genes and rep gene by inversion”, it is noted this limitation renders the claim indefinite since it is unclear if the claim means the cap genes and rep gene are part of the second module comprising AAV helper genes, which claim 1 indicates it is AAV helper genes that are under control of the second inducible regulatory element.
Regarding claim 20, it is noted that claim 20 recites the limitations:
“…AAV serotype-specific capsids (viral particles/mL)…” and
“…functional titer (transduction units/mL).”
The phrase "(viral particles/mL)" and the phrase “(transduction units/mL)” renders the claim indefinite because it is unclear whether the limitation(s) within the parentheses are part of the claimed invention, or are merely an example of the types of capsid titers or functional titers, respectively. The claim is unclear because the metes and bounds of the claim cannot be determined. See MPEP § 2173.05(d).
Appropriate clarification is required.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-2, 6, 12, 14, 20 and 21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lu 2024 (Lu et al. Biotechnol. J. March 2024, Vol. 19. DOI: 10.1002/biot.202400051 pp 1-12; IDS 9/9/2024).
Lu is directed to methods of producing rAAV producer cell lines that are integrated with essential viral genes which can be induced to produce rAAV, the method is scalable, robust and readily adaptable to rAAV vectors of other serotypes for use in gene therapy (Abstract and Introduction, page 2, right col, last paragraph to page 3, left col, first paragraph).
Regarding claim 1, Lu teaches the vector construction comprised constructing a genome module (GM), a replication module (RM), and a packaging module (PM) as illustrated at Figure S1A (see Lu’s Supplemental Materials, page 3; PTO-892) (“Lu Supplemental Materials”). Lu teaches the three vectors for GM, RM and PM were co-transfected into parental cell lines to develop the rAAV producer cells lines, i.e. a tunable adeno-associated virus (AAV) vector packaging cell line. Figure S1A is copied below for Applicant’s convenience:
PNG
media_image1.png
426
1344
media_image1.png
Greyscale
Lu teaches implementing a number of design features (See page 2, col 2, middle paragraph starting with “in the course of rAAV formation”):
using the Rep68 and Rep52 coding sequences placed under the control of inducible TetOn (Replication Module) and CumateSwitch control (Packaging Module), respectively;
A destabilization domain (DD) was linked to Rep68 to minimize its possible cytotoxicity caused by leaky expression;
Lu placed the cap gene under CumateSwitch control (removing p40) while also removing the intron and altering the translation initiation codon to adjust the VP1:VP2:VP3 ratio to be in line with the natural ratio in a capsid.
Lu’s Replication Module comprises a plurality of helper genes, i.e. E4orf6 and DBP (DNA-binding protein) under the control of the inducible TetON promoter (i.e. second inducible regulatory element) and reads on the claimed second module. Lu’s Replication Module further comprises Rep68 under the control of a separate TetON promoter (i.e., third inducible regulatory element), and thus Lu’s Replication Module reads on the claimed second and third modules.
Lu’s Packaging Module comprises cap genes VP123, under CumateSwitch control (removing p40) (i.e. first inducible regulatory element) while also removing the intron and altering the translation initiation codon to adjust the VP1:VP2:VP3 ratio to be in line with the natural ratio in a capsid.
Lu’s Packaging Module further includes Rep52 under CumateSwitch control which reads on the claimed first module.
Thus, Lu’s disclosed Replication Module and Packaging Module anticipates claim 1.
Regarding claims 2 and 14, Lu teaches the cell line of claim 1 further including a payload module containing an expressible gene encoding a vector payload, i.e., EGFP marker protein, located between two AAV inverted terminal repeat sequences and under control of the LacSwitch inducible regulatory element, thus anticipating claims 2 and 14.
Regarding claim 6, Lu’s disclosed Packaging Module includes Rep52 under control of the CumateSwitch control, thus anticipating claim 6.
Regarding claim 12, Lu’s Figure S1A illustrates the Replication Module comprises rtTA3, which reads on “at least one of said regulatory elements is a reverse tetracycline-controlled transactivator (rtTA)”, thus anticipating claim 12.
Regarding claim 19 and the limitation “wherein the progeny have been selected for amount of mitochondria content or reactive oxygen species per cell”, it is noted this limitation is directed to the manner by which the claimed cell line has been produced, i.e., selected for amount of mitochondria content or reactive oxygen species per cell. However, the instant claim is directed to a composition, per se.
Such limitations are product-by-process limitations which appear to define the claimed cell line. Product-by-process limitations are considered only insofar as the method of production imparts distinct structural or chemical characteristics or properties to the product. Therefore, if the product, as claimed, is the same or obvious over a product of the prior art (i.e., it is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985), and In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979). See also MPEP § 2113.
In the instant case, the method by which the cell line has been produced is not sufficiently detailed so as to impart any unique structural/chemical properties to the cell line.
If the product by process limitations are considered, the process imparts the feature of a packaging cell line comprising some amount of mitochondria or some amount of reactive oxygen species. Thus, any packaging cell line that contains any number of mitochondria or any number of reactive oxygen species would appear to read on the claimed cell line. Given that Lu teaches the same HEK-293 cells as disclosed in the instant application, it is considered that the cells of Lu will have the same properties of claim 19 and thus anticipate claim 19. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties Applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ 1655, 1658 (Fed. Cir. 1990).
Regarding claims 20 and 21, it is noted that Lu teaches that for rAAV2 production, the tunable packaging cell line was cultured in a medium containing 10 µg/mL of doxycycline and 90 µg/mL of cumate (i.e., a predetermined amount of the inducer compounds). Cells were harvested at 72 h post-induction (hpi). The production of rAAV2 by triple plasmid transfection followed the protocol in the product manual (VPK-402) provided by Cell Biolabs (2.3 Cell culture and rAAV production, page 3).
It is noted the inducible regulatory elements of Lu’s first, second and third modules are the TetON and CumateSwitch controls of the disclosed Replication Module and Packaging Module, which are inducted by Lu’s disclosed doxycycline and cumate, respectively. Thus, Lu’s teaching anticipates claim 21.
Further regarding claim 20, as set forth above, Lu anticipates claim 20, step (b).
As to claim 20, step (a), Lu further teaches transfecting the tunable packaging cells with the Genome Module (i.e., payload vector) comprising a gene encoding EGFP (i.e., a vector payload) between two AAV inverted terminal repeat sequences (ITRs), thus meeting the limitation of claim 20, step (a).
As to claim 20, step (c), Lu teaches optimizing the inducer compounds to adjust for TG (total intracellular virus genomes) and capsid ratios. Lu teaches shifting induction toward higher cumate concentrations increased capsids and VG (vector genome) levels (page 6, left col, first paragraph; page 7, right col, second paragraph; page 9, left col, last paragraph to right col, first paragraph).
Thus, Lu’s teaching anticipates claim 20.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 3-5 are rejected under 35 U.S.C. 103 as being unpatentable over by Lu, as applied to claims 1-2, 6, 12, 14, 20 and 21 above and further in view of McDonnell (WO 99/46371 pub date 3/11/1999; see PTO-892) (“McDonnell”).
Lu anticipates claims 1-2, 6, 12, 14, 20 and 21.
Regarding claim 3-4, Lu does not teach that the packaging cell line encodes an apoptosis inhibitor protein under control of an inducible promoter (claim 3), more particularly Bcl-2 (claim 4). However, McDonnell is directed to viral expression vectors for transforming mammalian cells for use in cancer therapy (Abstract). McDonnell teaches the use of viral vectors to deliver Bcl-2 family apoptosis regulatory elements as a payload to cells. McDonnell teaches that the Bcl-2 gene was long known in the prior art as an anti-apoptotic gene that results in augmented cellular proliferation and p53 mediated cell death induction is blocked in cells transformed with Bcl-2 (pages 23-24).
Thus, it would have been obvious to one of ordinary skill at the time of effectively filing to use the Bcl-2 gene, taught by McDonnell, as the payload gene in the AAV producer cell line of Lu, to predictably arrive at the limitations of claims 3-4. The artisan would have a reasonable expectation of success because the Bcl-2 transgene was well established in the prior art and could be incorporated into the payload of Lu using methods described in both Lu and McDonnell. Further, an artisan would have been motivated to use the Bcl-2 transgene as the payload because McDonnell teaches anti-apoptotic gene that results in augmented cellular proliferation in cells transformed with Bcl-2, thus improving the growth and proliferation of the desired producer cell line.
Regarding claim 5, Lu teaches claim 1 as discussed above. Lu does not teach that the regulatory element is an ecdysone receptor fusion protein. However, long before the effective filing date, ecdysone receptor fusion proteins were well established in the prior art. McDonnell is directed to viral expression vectors for transforming mammalian cells for use in cancer therapy (Abstract). McDonnell teaches:
“The ecdysone system (Invitrogen, Carlsbad, CA) is one such system. This system is designed to allow regulated expression of a gene of interest in mammalian cells. It consists of a tightly regulated expression mechanism that allows virtually no basal level expression of the transgene, but over 200-fold inducibility. The system is based on the heterodimeric ecdysone receptor of Drosophila, and when ecdysone or an analog such as muristerone A binds to the receptor, the receptor activates a promoter to turn on expression of the downstream transgene high levels of mRNA transcripts are attained. In this system, both monomers of the heterodimeric receptor are constitutively expressed from one vector, whereas the ecdysone-responsive promoter which doves expression of the gene of interest is on another plasmid engineering of this type of system into the gene transfer vector of interest would therefore be useful co-transfection of plasmids containing the gene of interest and the receptor monomers in the producer cell line would then allow for the production of the gene transfer vector without expression of a potentially toxic transgene. At the appropriate time, expression of the transgene could be activated with ecdysone or muosteron A.” (pages 51-52).
Therefore, it would have been obvious to one of ordinary skill art before the time of effective filing to modify the AAV producer cell of Lu to use an ecdysone receptor fusion protein inducible promoter system, as taught by McDonnell, as one of the inducible promoters, particularly with one of the toxic rep genes, to predictably arrive at the limitations of claim 5. The skilled artisan would have a reasonable expectation of success because the ecdysone inducible promoter system has been long established in the prior art and has been used with viral vectors and producer cell lines. Further, the skilled artisan would be motivated to use the ecdysone inducible promoter system because McDonnell teaches the system is designed to allow regulated expression of a gene of interest in mammalian cells and it consists of a tightly regulated expression mechanism that allows virtually no basal level expression of the transgene, but over 200-fold inducibility.
The combination of prior art cited above in the rejection under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the instant case, rationales A, B and G are applicable. The claimed cell line was known in the art at the time of filing as indicated by Lu, in view of McDonnell. Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Further regarding claim 11 and the limitation the apoptosis inhibitor protein (gene of interest) is under control of both first and second inducible regulatory elements, Lu does not further teach the gene of interest is under control of the CumateSwitch (first inducible regulatory element) and TetON (second inducible regulatory element). However, it is noted that Lu’s gene of interest comprises a Lacl inducible promoter, in addition to the LacSwitch control, for the gene of interest (GOI) in order to suppress excessive expression of the gene of interest (page 11, left col, third paragraph). Thus, Lu has established it was known that the gene of interest can be controlled by two inducible regulatory elements, and Lu has demonstrated that CumateSwitch and TetON are suitable regulatory elements.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute alternative inducible regulatory elements, as taught by Lu, since both are known to provide inducible gene expression. Therefore, one of ordinary skill in the art would recognize this as simply substituting one type of inducible regulatory element for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over by Lu, as applied to claims 1-2, 6, 12, 14, 20 and 21 above.
Lu anticipates claims 1-2, 6, 12, 14, 20 and 21.
Regarding claim 7, it is noted as set forth above regarding the rejection of claim 1, the second inducible regulatory element, of the second module (Replication Module), is considered the disclosed TetON control element as illustrated in Lu’s Figure S1A. Further, as discussed above regarding claim 1, Lu’s Packaging module discloses the VP123 (cap genes) and Rep52 (rep gene) are under the control of the CumateSwitch. Lu does not further teach the VP123 (cap genes) and Rep52 (rep gene) of the Packaging Module further including TetON control. However, Lu’s Packaging module does further comprise the CymR regulatory element. Thus, Lu has established that the cap genes and rep gene are under control of additional regulatory elements, in addition to the CumateSwitch that is induced by the presence of cumate.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ additional regulatory elements for controlling the disclosed cap genes and rep gene.
The person of ordinary skill in the art would have been motivated to modify the composition of Lu to include the additional regulatory element for controlling the disclosed cap genes and rep gene for the predictable result of successfully optimizing expression of the cap genes and rep gene since the intention of Lu is to minimize cytotoxicity related to leaky expression (page 2, col 2, middle paragraph), thus meeting the limitation of claim 7.
The rationale to support this conclusion of obviousness is that the single reference provides the teachings and suggestion to include the additional regulatory element for controlling the disclosed cap genes and rep gene. Furthermore, there is no evidence on the record that shows that the claimed limitation has any greater or unexpected results than that exemplified by Lu.
Claims 8-10 are rejected under 35 U.S.C. 103 as being unpatentable over Lu, as applied to claims 1-2, 6, 12, 14, 20 and 21 above, and further in view of Juchheim et al., (addgene Blog, Plasmids 101:Cre-lox, published January 13, 2015, retrieved from the internet; see PTO-892) (“Juchheim”).
Lu anticipates claims 1-2, 6, 12, 14, 20 and 21.
Regarding claims 8-10, it is noted that Lu’s second regulatory element is TetON (inducible with doxycycline). Lu does not further teach the disclosed regulatory elements as recited in claims 8-10. However, Juchheim is directed to a discussion of the Cre-lox system that uses Cre recombinase and a loxP recognition site (ligand binding domain) for genome manipulation (What is Cre-lox?, first paragraph, page 1). Juchheim (page 3) illustrates the Cre-lox inversion technique for controlling expression. Juchheim teaches that regulated Cre expression can be placed downstream of promoters and used by making the Cre inducible with doxycycline and thus Cre recombinase is expressed at specified times (page 4). Thus, Juchheim has established that Cre-lox is a well-known genome manipulation tool and is an inducible regulatory element for controlling gene expression by inversion.
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to substitute Cre-lox for the TetON inducible regulatory element since both are known inducible regulatory elements for manipulating gene expression, inducible by doxycycline. Therefore, one of ordinary skill in the art would recognize this as simply substituting one type of doxycycline inducible regulatory element for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Lu and Juchheim because each of these teachings are directed at plasmid construction for genome manipulation.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Lu, as applied to claims 1-2, 6, 12, 14, 20 and 21 above, and further in view of Juchheim (cited above) and McDonnell (cited above).
Lu, anticipates claims 1-2, 6, 12, 14, 20 and 21.
Regarding claim 13, as set forth above at the rejection of claim 12, Lu’s Figure S1A illustrates the Replication Module comprises two TetOn regulatory elements as well as rtTA3 (reverse tetracycline-controlled transactivator). At the rejection of claim 1, Lu’s TetON regulatory element controlling Rep68 expression was considered the third regulatory element. However, it is noted that Lu’s disclosed rtTA alternatively reads on a third regulatory element, thus meeting the limitation of claim 13.
Further as to the limitation the first regulatory element is an ecdysone receptor fused to a DNA binding domain, it is noted, as discussed at the rejection of claim 5, that Lu, in view of McDonnell, renders obvious said limitation.
Additionally, as to the limitation regarding the second regulatory element is a Cre recombinase enzyme with a ligand binding domain, it is noted, as discussed above at the rejection of claims 8-10, Lu, in view of Juchheim render obvious the second regulatory element is a Cre recombinase enzyme with a ligand binding domain.
Therefore, it would have been obvious to one of ordinary skill art before the time of effective filing to modify the AAV producer cell of Lu to use well-known expression regulatory elements, specifically using an ecdysone receptor fusion protein inducible promoter system as the first regulatory element, as taught by McDonnell, and the second regulatory element is a Cre recombinase enzyme with a ligand binding domain, as taught by Juchheim.
The skilled artisan would have a reasonable expectation of success because the ecdysone inducible promoter system and the Cre recombinase inducible regulatory system have been long established in the prior art and have been used with viral vectors and producer cell lines. Further, the skilled artisan would be motivated to use these well-known gene expression regulatory systems because McDonnell and Juchheim teach theses systems are designed to allow regulated expression of a genes in mammalian cells thus providing tightly regulated expression mechanisms.
The combination of prior art cited above in the rejection under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the instant case, rationales A, B and G are applicable. The claimed cell line was known in the art at the time of filing as indicated by Lu, in view of McDonnell and Juccheim. Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over by Lu, as applied to claims 1-2, 6, 12, 14, 20 and 21 above, and further in view of Hu et al., (US 2023/0279427; see PTO-892) (“Hu”).
The teaching of Lu is set forth above and anticipates claims 1-2, 6, 14, 20 and 21.
Regarding claim 15, it is noted that Lu does not specifically teach that the payload is an immunogenic peptide or nucleic acid encoding said peptide for eliciting an immune response. However, Hu is directed to producer cell lines (e.g., HEK-293) for AAV protein production (Abstract and [0006]). Hu teaches the mammalian cell line includes recombinantly inserted transgenes having at least three modules, and further includes a gene of interest flanked by AAV inverted terminal repeats, wherein the gene of interest is a polynucleotide encoding a protein (FIGs 1A-1D and 2A-2D; [0007]-[0012]).
The gene of interest may include marker proteins [0054], or immunoglobulins ([0128]-[0129]), e.g., IgG light chain or heavy chain(FIG. 3A, [0036]).
As such, it would have been obvious to one of ordinary skill at the time of effectively filing to substitute an immunogenic protein, i.e., IgG light or heavy chain, as the gene of interest in Lu, as taught by Hu, in order to produce therapeutic immunoglobulin proteins for gene therapy.
The person of ordinary skill in the art would have been motivated to substitute immunogenic protein, i.e., IgG light or heavy chain, as the gene of interest for the predictable result of successfully producing immunoglobulins for therapeutic use, thus meeting the limitation of claim 15.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Lu and Hu because each of these teachings are directed at AAV vector packaging cell lines for AAV and AAV protein production.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over by Lu, as applied to claims 1-2, 6, 12, 14, 20 and 21 above, and further in view of Gu et al., (US 2020/0199627; see PTO-892) (“Gu”).
The teaching of Lu is set forth above and anticipates claims 1-2, 6, 12, 14, 20 and 21.
Regarding claim 16, it is noted that Lu does not specifically teach that the payload is a nucleic acid encoding a gene product that is deficient in a subject in need of gene therapy. However, Gu is directed to AAV producer cell lines for long-term and cost-effective solutions for large-scale AAV manufacturing (Abstract and [0068]). The cell lines further include nucleic acids encoding a gene of interest under the control of inducible regulatory elements ([0012]-[0013]). The gene of interest, e.g. EGFP, is flanked by inverted terminal repeat sequences (ITRs) ([0060]-[0061]) and Gu teaches the gene of interest can be those that encode a protein that is defective or missing from a target cell genome and thus provide a therapeutic protein ([0066]).
As such, it would have been obvious to one of ordinary skill at the time of effectively filing to substitute a therapeutic protein that is defective or missing from a target cell genome, as the gene of interest in Lu, as taught by Gu, in order to produce the deficient protein for gene therapy.
The person of ordinary skill in the art would have been motivated to substitute a therapeutic gene of interest that is defective or missing from a target cell genome, as the gene of interest for the predictable result of successfully improving the gene deficiency, thus meeting the limitation of claim 16.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Lu and Gu because each of these teachings are directed at AAV producer cell lines.
Claims 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Lu, as applied to claims 1-2, 6, 12, 14, 20 and 21 above and further in view of Forman et al., (U.S. Patent No. 11,649,449; IDS 9/9/2024) (“Forman”).
Lu anticipates claims 1-2, 6, 12, 14, 20 and 21.
Regarding claims 17-18, Lu discloses that the packaging cell line is a modified HEK-293 cell line (page 2, col 2, middle paragraph starting with “in the course of rAAV formation”; and 2.3 Cell culture and rAAV production, page 3), however Lu differs from the instant invention in that Lu does not further teach the packaging cell line is the progeny of a fusion of two or more parental cell lines (claim 17), or is a progeny of a fusion of two HEK-293 cells (claim 18).
However, Forman is directed to producer cell lines for manufacture of protein-based pharmaceutical agents (Abstract). The cell lines are transfected with a gene of interest for producing the protein-based pharmaceutical (col. 8, lines 4-8). Forman further teaches the producer cells can be subjected to one or more cycles of fusion and selection (col 4, lines 49-51), and model cells for fusion are cell lines such as HEK-293 cells (col 5, lines 44-48). Cell fusion is performed by obtaining a plurality of cells from one cell line, or more than one cell line (i.e., parental cell line) (col 5, lines 62-65).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to conduct fusion of two or more parental cell lines, specifically HEK-293 cells, thus meeting the limitation of claims 17-18.
The person of ordinary skill in the art would have been motivated to modify the producer cell line of Lu to include cell fusion, as taught by Forman, for the predictable result of preparing a producer cell line for the manufacture of protein-based pharmaceuticals.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Lu and Forman because each of these teachings are directed at producer cell lines.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to E. YVONNE PYLA whose telephone number is (571)270-7366. The examiner can normally be reached M-F 9am - 6pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, CHRISTOPHER BABIC can be reached at 571-272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633