DETAILED ACTION
Applicant’s response filed 6/29/2026 has been received and entered into the application file. All arguments have been fully considered. Claims 1-21 are currently pending. Claims 1-3, 5-7,9-15, 17, 19-20 are currently amended.
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.
REJECTIONS WITHDRAWN
Claim Rejections - 35 USC § 112
RE: Rejection of Claims 7, 10 and 20 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite:
Regarding claims 7 and 10, Applicant’s amendment submitted 6/29/2026 has clarified the first module recited in claim 6 comprises a plurality of cap genes and at least one AAV rep gene situated in the first module, and the transcription of the cap and rep genes in the first module are also under control of the second inducible regulatory element in the second module. Applicant’s amendment provides sufficient clarification. Therefore, the rejection of claims 7 and 10 are withdrawn.
Regarding claim 20, it is noted the phrase "(viral particles/mL)" and the phrase “(transduction units/mL)” have been removed, thus obviating the previous rejection of record. Therefore, the rejection of claim 20 is withdrawn.
Claim Rejections - 35 USC § 102
RE: Rejection of Claim(s) 1-2, 6, 12, 14, 20 and 21 under 35 U.S.C. 102(a)(1) as being anticipated by Lu 2024 (IDS 9/9/2024):
The rejection of record is withdrawn in view of Applicant’s amendment submitted 6/29/2026, which now requires each of said three modules is not contiguous with either of the other modules; and wherein each of said inducible regulatory elements is inducible by a small molecule inducer compound that is different from the inducer compounds for the other inducible regulatory elements.
Lu’s disclosed helper gene and Rep68 gene located in the replication module were both under inducible control by TetON. However, Applicant’s amendment has necessitated new grounds of rejection as set forth below.
Claim Rejections - 35 USC § 103
RE: Rejection of Claim(s) 3-5 under 35 U.S.C. 103 as being unpatentable over by Lu, and McDonnell;
Rejection of Claim 7 under 35 U.S.C. 103 as being unpatentable over by Lu:
Rejection of Claims 8-10 under 35 U.S.C. 103 as being unpatentable over Lu, and Juchheim;
Rejection of Claim 13 under 35 U.S.C. 103 as being unpatentable over Lu, and further in view of Juchheim (cited above) and McDonnell;
Rejection of Claim 15 under 35 U.S.C. 103 as being unpatentable over by Lu, and further in view of Hu;
Rejection of Claim 16 under 35 U.S.C. 103 as being unpatentable over by Lu, and further in view of Gu;
Rejection of Claims 17-18 under 35 U.S.C. 103 as being unpatentable over Lu, and further in view of Forman:
For the reasons discussed above, the anticipation rejection over Lu et al is withdrawn, and thus the obviousness rejections that are based on the same basis are likewise withdrawn. However, the amendment submitted 6/29/2026 has necessitated new grounds of rejection, as set forth below.
New Ground(s) of Rejection, Necessitated by Amendment
Claim Rejections - 35 USC § 112
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.
Claim 5 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Claim 5 has been amended to recite the following:
5. The tunable packaging cell line of claim 1 wherein each of the three modules is integrated into three separate regions of the genome of the packaging cell line.
Applicants point to FIG. 1 and paragraph [0012] of the instant specification to support the amendment to claim 5. However, it is noted that FIG. 1 and paragraph [0012] do not disclose that the three modules are integrated into three separate regions of the genome of the packaging cell line. No experimental data is present in the original disclosure to show integration of the three modules into three separate regions of the cell genome. Therefore, the limitation that each of the three modules is integrated into three separate regions of the genome of the packaging cell line is considered new matter.
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 and 20-21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lee et al., (ACS Synth. Biol. 2022, 11, 3285-3295; see PTO-892) (“Lee”), as evidenced by Re et al., (Experimental Hematology 32 (2004) 210-217; see PTO-892) (“Re”).
Lee is directed to methods of constructing rAAV producer cell lines via synthetic biology, wherein three modules were integrated into HEK293 cells including an rAAV genome and multiple inducible promoters independently controlling the expression of AAV Rep, Cap and helper genes, thus permitting tunable control of gene expression profiles that enhance the quality of viral vector production, i.e., tunable adneo-associated virus (AAV) vector packaging cell lines (Abstract).
Regarding claim 1, Lee teaches the intention was to employ separate control of the different viral component expression levels in order to achieve a higher full capsid content of the produced vector, which required the following essential components:
a genome module (GM) containing a rAAV genome including the gene of
interest (represented by mark protein GFP);
a replication module (RM) providing the large Rep protein of AAV and helper proteins of Ad; and
a packaging module (PM) for expressing capsid proteins and the small Rep protein as illustrated at Figure 1A. Figure 1A is copied below for Applicant’s convenience:
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Lee’s Figure 1A teaches a number of design features as follows:
Lee teaches the Packaging module construct comprising at least one AAV cap gene under CumateSwitch transcriptional control (i.e., first module and first inducible regulatory element);
Lee’s Replication module comprises helper genes, i.e. E4orf6 and DBP (DNA-binding protein) under the control of the inducible GeneSwitch promoter (i.e. second module and second inducible regulatory element). Lee’s Replication module further comprises Rep68 under the control of an inducible TetON promoter (i.e., third module and third inducible regulatory element).
Figure 1A illustrates that E4orf6 and DBP are not contiguous with Rep68 or the cap genes, and each of the inducible promoters are different from each other.
Thus, Lee’s disclosed constructs anticipate claim 1.
Regarding claims 2 and 12-14, Lee teaches the cell line of claim 1 further including a payload module that is separate from said first, second, and third modules, which contains 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 CAG regulatory element, and Re evidences that EGFP is an immunogenic peptide and suggests its use to enhance the expansion of tumor-specific T cells (Abstract, Conclusions; page 210, left col, last 2 lines; page 210, right col, second paragraph). Thus, Lee anticipates claims 2 and 12-14.
Regarding claim 6, Lee’s disclosed Packaging module construct includes Rep52 under transcriptional control of the CumateSwitch inducible regulatory element, thus anticipating claim 6.
Regarding claims 20 and 21, it is noted that Lee teaches that for rAAV2 production, the tunable packaging cell line was cultured in a medium containing 10 µg/mL of doxycycline, mifepristone at 2.5 nM and 10 µg/mL or 90 µg/mL of cumate (i.e., different amounts of inducer compounds, predetermined amounts) (Figure 4; page 3291, left col, second paragraph and right col, second paragraph).
It is noted the inducible regulatory elements of Lee’s first, second and third modules are CumateSwitch, GEneSwitch and TetON controls respectively, which are induced by Lee’s disclosed cumate, mifepristone and doxycycline, respectively. Thus, Lee’s teaching anticipates claim 21.
Further regarding claim 20, as set forth above, Lee anticipates claim 20, step (b).
As to claim 20, step (a), Lee 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), Lee teaches optimizing the inducer compounds by varying inducer levels and altering the ratio of various viral components resulting in changing the properties of the produced viral particles, specifically high cumate induction gave high particle yield but smaller proportion of particles containing genome, while full dox induction favored high genome amplification. Conversely, lower cumate concentration and fully induced dox level resulted in low particle titer and a higher level (73%) of full capsids (Figure 4C). Using the traditional triple transfection method, Lee obtained approximately 35% full capsid content (Figure 4C and page 3291, right col, second paragraph).
Thus, Lee’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) 3-4 are rejected under 35 U.S.C. 103 as being unpatentable over by Lee, 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; previously cited) (“McDonnell”).
Lee anticipates claims 1-2, 6, 12-14, 20 and 21.
Regarding claim 3-4, although Lee acknowledges one of the challenges of GMP plasmid preparation is cytotoxicity and there are alternative technologies that address the issue by integrating necessary components into the host genome, Lee does not teach that the packaging cell line encodes an apoptosis inhibitor protein under transcriptional control of one of said inducible regulatory elements (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 Lee, 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.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over by Lee, as applied to claims 1-2, 6, 12-14, 20 and 21 above and further in view of ASGCT-FDA Liaison Meeting (November 8, 2021, 19 pages, retrieved from the internet; see PTO-892) (“ASGCT”).
Regarding claim 5, and the limitation “wherein each of the three modules is integrated into three separate regions of the sequence of the packaging cell line”, it is noted that Lee does not further comment on integration locations. However, ASGCT is directed to integration/insertion considerations for AAV-based gene therapy vectors and teaches that rAAV integration is generally random, but favored in actively transcribed regions of the genome (rAAV Integration Frequencies, Takeaways, page 5).
Therefore, it is reasonable to consider, absent evidence to the contrary, that each of the three prior art modules are integrated into three separate regions of the genome of the the packaging cell line, thus meeting the limitation of claim 5.
Claims 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Lee, 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; previously cited) (“Juchheim”).
Lee anticipates claims 1-2, 6, 12-14, 20 and 21.
Regarding claim 8, Lee does not further teach the disclosed regulatory elements include a recombinase enzyme with a ligand binding domain. 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, given that Lee notes that the GeneSwitch promoter did not show a wide range of dynamics in controlling transcript levels or rAAV titer, 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 GeneSwitch inducible regulatory element since both are known inducible regulatory elements for manipulating 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). One would have been motivated to substitute Cre-lox for the GeneSwitch inducible promoter in order to provide greater transcriptional control,
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Lee and Juchheim because each of these teachings are directed at plasmid construction for genome manipulation.
Claim 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over by Lee, as applied to claims 1-2, 6, 12-14 and 20-21 above, and further in view of Qin et al., (Front Cell Infect Microbiol. 2022 Mar 3;12:802147; see PTO-892) (“Qin”).
Lee anticipates claims 1-2, 6, 12-14, 20 and 21.
Regarding claim 15, it is noted that claim 15 now recites the limitation “wherein upon administration a subject in need thereof, the vector payload induces a specific response to the SARS-COV-2, the virus that causes COVID-19.”
It is noted said limitation is directed to the intended use of the vector payload to induce a specific response to SARS-COV-2, the virus that causes COVID-19. Thus, it is considered that the payload comprises components that would elicit a response to the SARS-COV-2 strain of coronavirus.
Lee does not further teach the immunogenic payload comprises components that would elicit a response to the SARS-COV-2 strain of coronavirus. However, Qin teaches developing a type 9 adeno-associated virus (AAV) vectored vaccine candidate expressing a dimeric receptor binding domain (RBD) of the SARS-CoV-2 spike protein (S protein) (AAV9-RBD) and evaluated its immunogenicity in a murine model. AAV9-RBD was packaged in a HEK293 cell line for SARS-COV-2 vaccine therapy (Abstract; Packaging of the Recombinant Adeno-Associated Virus, left col, page 3; The Expression and Identification of Recombinant AAV9-RBD Virus, page 5; Figure 2).
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 a dimeric receptor binding domain (RBD) of the SARS-CoV-2 spike protein, as taught by Qin, as the payload in the packaging cell line of Lee.
The person of ordinary skill in the art would have been motivated to prepare an AAV packaging cell line comprising components that would elicit an immune response to the SARS-COV-2 for the predictable result of providing an effective therapy for combating SARS-COV 2 infection.
The skilled artisan would have had a reasonable expectation of success in substituting the dimeric receptor binding domain (RBD) of the SARS-CoV-2 spike protein because Qin has shown successfully packaging AAv9-RBD in HEK-293 cells.
Regarding claim 16, Qin immunizes mice deficient for RBD antibodies prior to immunization (Figure 5), thus meeting the limitation of claim 16.
Claims 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Lee, as applied to claims 1-2, 6, 12-14 and 20-21, above and further in view of Forman et al., (U.S. Patent No. 11,649,449, previously cited; IDS 9/9/2024) (“Forman”).
Lee anticipates claims 1-2, 6, 12-14, 20 and 21.
Regarding claims 17-18 it is first noted that claim 17 has been amended to now recite the limitation “which is the progeny of a hybrid cell made by a process that comprises fusion of two or more cells from a parental cell line.” Said limitation is directed to the manner by which the packaging cell line has been produced. 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, if the product by process limitations are considered, the process imparts the feature of the packaging cell line being fused cells. Thus, any packaging cell line comprising fused cells would appear to read on claim 17.
Lee teaches RP6 and RP7 packaging cell lines (Figure 3) and HEK-293 packaging cell lines (page 3289, right col, last paragraph).
Lee differs from the instant invention in that Lee does not further teach the packaging cell line is the progeny of a fusion of two or more cells from 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.
Regarding claim 19 and the limitation “wherein said process comprises selecting cell hybrid to enrich 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, 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 mitochondria or any number of reactive oxygen species would appear to read on the claimed cell line. Given that Forman renders obvious HEK-293 fusion cells, it is considered, absent evidence to the contrary, that the HEK-293 fusion cells comprise mitochondria, thus meeting the limitation of claim 19.
Allowable Subject Matter
Claims 7 and 10-11 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Response to Remarks
As to Applicant’s remarks regarding the cited reference to McDonnell, it is noted that Applicant’s remarks have been fully considered but are not found persuasive since the claims as currently drafted do not exclude Bcl-2 from a payload module.
Further as to Applicant’s remarks regarding the cited reference to Juchheim, Applicant asserts that Juchheim does not teach or suggest use of gene inversion as part of a tunable gene control. However, Applicant’s remarks are not found persuasive since Juchheim illustrates the Cre-lox inversion technique for controlling expression.
Applicant’s remarks regarding the cited reference to Forman have been carefully considered, but are not found persuasive since Lee and Forman are directed to packaging therapeutic products in HEK293 cells.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
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