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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 21, 2025 has been entered.
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on July 21, 2025. Claims 1, 3-18 and 20-22 are pending. Claims 5, 8, 12, 14-15 and 17-18 are withdrawn. Claims 1, 3-4, 6-7, 9-11, 13, 16 and 20-22 are currently examined.
Claim Rejections - 35 USC § 112 (Written Description)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
(Previous rejection- maintained with the addition of claims 21-22) Claims 1, 3-4, 6-7, 9-11, 13, 16 and 20 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.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. However, a showing of possession alone does not cure the lack of a written description. Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 969-70, 63 USPQ2d 1609, 1617 (Fed. Cir. 2002). For example, it is now well accepted that a satisfactory description may be found in originally-filed claims or any other portion of the originally-filed specification. See In re Koller, 613 F.2d 819, 204 USPQ 702 (CCPA 1980); In re Gardner, 475 F.2d 1389, 177 USPQ 396 (CCPA 1973); In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). However, that does not mean that all originally-filed claims have adequate written support. The specification must still be examined to assess whether an originally-filed claim has adequate support in the written disclosure and/or the drawings. See MPEP 2163. I.
In Regents of the University of California v. Eli Lilly and Co. 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997), the Court decided that adequate written description of genetic material "requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention." Id. 43 USPQ2d at 1404 (quoting Fiefs, 984 F.2d at 1171, 25 USPQ2d at 1606). In AbbVie Deutschland GMBH & Co. v. Janssen Biotech, Inc. (Court of Appeals, Federal Circuit 2014), the Court ruled that “[W]ith the written description of a genus, however, merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus. See Ariad, 598 F.3d at 1353 (The written description requirement guards against claims that “merely recite a description of the problem to be solved while claiming all solutions to it and . . .cover any compound later actually invented and determined to fall within the claim' s functional boundaries.”).”
The base claims 1 and 20 are directed to a viral vector or viral particle packaging cell line, wherein each cell is progeny of a hybrid cell that constitutes a fusion of two or more parental cells from a starting cell line; wherein the starting cell line is characterized as being capable of producing a viral vector or particle when transfected to express viral genes that encode the viral vector or particle; wherein the packaging cell line already contains said viral genes, and produces at least 2-fold more of the viral vector or particle per volume of culture fluid than does the starting cell line when transfected to express the same viral genes.
The instant specification discloses using CHO and HEK 293 cells to generate the fusion packaging cell lines (See [0144] to [0156]), and the produced viral vectors are AAV and Lentivirus (See [0160] to [0166]). In Example 1, the instant specification discloses that the expression of the marker protein (SEAP) in the fused cells shows over 4-fold improvement (See [0155]), but it is not clear if this measurement is on the per volume of culture fluid as claimed. Fig. 10 of the instant application discloses a higher productivity of capsids of several serotypes of AAV vectors from fused HEK 293 cells. Engineered clone (17-2) showed 3-fold, 9-fold, and 2.5-fold increase of AAV vectors compared with parent host cells, respectively (See [0033]), which teaches the increased viral particle fold but it is not clear if this is on per volume of culture fluid as claimed. Also, the instant specification only discloses using specific cell lines such as CHO and HEK 293 cell lines to produce the specific viral production of AAV and Lentivirus that can lead to a higher production comparing with their parent cell lines. Furthermore, the increased viral particle/vector folds in the example and Figures are not disclosed as a per volume of culture fluid. Because the instant claims are directed to a generic cell, generic viral vector and limitation of per volume of culture fluid, the instant specification does not provide evidence to demonstrate and support if any other cell line can be used as a fusion cell line to produce any other viral particles at least 2-fold more of the viral vector or particle per volume of culture fluid than does the starting cell line when transfected to express the same viral genes. Furthermore, the instant specification does not provide a description to show the increased folds are at a per volume of culture fluid.
Based on the description above, the skilled artisan cannot envision the detailed method/process for producing and purifying any rhabdovirus using any cell line and any viral release agent. Therefore, the full breadth of the claims does not meet the written description provision of 35 U.S.C. 112, first paragraph.
Accordingly, the specification does not provide sufficient written description support for the invention as claimed the base claims 1 and 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.
(Previous rejection- maintained) Claims 1, 6-7, 9-10, 13 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Kondo et al. (2004 Nov;35(5):1120-6) and further in view of Li et al. (Electron J Biotechnol. 2019 Sep; 41:56-59).
The base claims 1 and 20 are directed to a viral vector or viral particle packaging cell line, wherein each cell is progeny of a hybrid cell that constitutes a fusion of two or more parental cells from a starting mammalian cell line; wherein the starting cell line is characterized as being capable of producing a viral vector or particle when transfected to express viral genes that encode the viral vector or particle; wherein the packaging cell line already contains said viral genes, and produces at least 2-fold more of the viral vector or particle per volume of culture fluid than does the starting cell line when transfected to express the same viral genes, where the claim 20 further requires that the starting cell line are transfected to express said viral genes and a transgene encoding a payload, the packaging cell line produces at least 2-fold more of the viral vector or particle that encapsulates the payload than does the starting cell line.
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Kondo et al. describes a study on detection of osteoclastic cell–cell fusion through retroviral vector packaging, and teaches two model systems demonstrating that cell–cell fusion results in retrovirus production when one cell contains defective retroviral vector and the other produces proteins for retroviral packaging (See page 1124, right column, paragraph 2). In one model system, Kondo et al. discloses using CHO cells as the starting cell line (See Fig. 1, page 1122 and below), and the vectors are the retroviral vectors, pBabe puro and pFB neo (Stratagene), which express inserted genes from the MLV long terminal terminal repeat (LTR) (See page 1121, left column, paragraph 4). CHO cell lines are transfected with the retroviral vectors and cell–cell fusion is triggered by interaction between Env expressed on CHOpac cells and the receptor mCAT-1 on CHOmcat cells. CHOpac cells produced Env as well as Gag and Pol, and a specialized vector cell, CHOmcat, carried a retroviral vector expressing mCAT-1-GFP. Fusion between CHOpac and CHOmcat was detected by a novel cell fusion assay and fusion of these two cell types results in release of infectious retroviral particles into culture supernatant (See Fig. 1 above; page 1121, right column, paragraph 2; page 1124, right column, paragraph 3).
Accordingly, Kondo et al. teaches a viral vector or viral particle packaging cell line, where each fused cell is from CHO cells containing viral genes, and the cell–cell fusion can result in the production of infectious retroviruses carrying a fusion-inducing gene. Here the CHO cell is a widely used cell line for producing large quantities of recombinant proteins, including particles like viral vectors or virus-like particles, which teaches the limitations in the instant claims. As an example of evidence of CHO cells used as a packaging cell line, Li et al. teaches retrovectors packaged in CHO cells to generate GLP-1-Fc stable expression CHO cell lines (See Title). Li et al. teaches a CHO cell transfection using a transfer plasmid (pRDM-GLP-1-Fc or pLEGFPC1) and packaging plasmids pMD2.G and pCMV-gag-pol, and then CHO cell transduction and stable cell line generation (See page 57, left column, paragraphs 3 & 4; right column, paragraphs 1 & 2). Li et al. teaches that suspension CHO cells are relatively safe, clean, and reliable packaging cells for retrovectors. Generation of CHO stable cells with these retrovectors eliminates virus contamination from serum and traditional packaging cells such as HEK-293 (See page 59, left column, paragraph 4; right column, paragraph 1).
As for the limitation of “produces at least 2-fold more of the viral vector or particle per volume of culture fluid than does the starting cell line”, Kondo et al. does not specifically teach the 2-fold more viral vector or particle, however, Kondo et al. expressed GAL4-VP16 in CHOpac and the luciferase reporter in CHOmcat cells. As shown in Fig. 3, luciferase activity was significantly elevated 24 h after co-culturing CHOmcat and CHOpac cells comparing the transfection to the parent CHO cells, suggesting that fusion had occurred between these two types of cells (See page 1122, right column, paragraph 1; Fig. 3, page 1123 and below), which indicates 2-fold more of the viral vector or particle is produced comparing to the starting cell line CHO at 24 hours.
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Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Regarding claims 6-7, they require packaging cell line also contain a transgene where the packaging cell line produces a greater percentage of viral vectors or particles containing that contain said payload compared to the start cells. Kondo et al. teaches the fused CHO cell line express the MLV retroviral vector inserted with a payload gene of Gal4-VP16 and luciferase (See page 1121, right column, paragraph 2; Fig. 3 above), and the luciferase expression shows more than 2-fold increasing at 24 h in the fusion cell lines (See Fig. 3, above and page 1122, right column, paragraph 1).
Regarding claim 9, it requires that the payload includes a nucleic acid that encodes enhanced green fluorescent protein (eGFP) or another protein that emits a detectable signal. Kondo et al. teaches that the vector CHOmcat carried a retroviral vector expressing mCAT-1-GFP.
Regarding claims 10 and 13, they require that the payload is a pharmaceutical agent and the nucleic acid for gene therapy of a subject in need. Kondo et al. teaches the lentiviral vector containing the payload gene but the gene is not specific for therapy. However, Li et al. teaches that the CHO packaging cell line expresses glucagon-like peptide-1 Fc fragment fusion protein (GLP-1-Fc), a long-acting GLP-1 analog for type 2 diabetes. The yield of GLP-1-Fc recombinant protein can reach 3.15 g/L. GLP-1-Fc produced from this method has comparable bioactivity to that of commercial GLP-1-Fc (dulaglutide) (See page 57, left column, paragraph 2). It would be obvious for one of ordinary skill in the art to add GLP-Fc into Kondo’s cell-cell fusion CHO cell system to express the GLP-Fc if a therapy of a type 2 diabetes patient is needed. One of skill in the art would have been motivated to do so if a high yield of GLP-1-Fc is needed for treating diabetes patient. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated and commonly used as evidenced by the prior art teachings.
(Previous rejection- maintained) Claims 3, 4 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Kondo et al. (2004 Nov;35(5):1120-6) as evidenced by Li et al. (Electron J Biotechnol. 2019 Sep;41:56-59) as applied to claims 1, 6-7, 9-10, 13 and 20 above, and in view of Landgrebe et al. (BMC Proc. 2011 Nov 22;5 Suppl 8(Suppl 8):P83) and Chakrabarti et al. (MAbs. 2022 Jan-Dec;14(1):2020081).
Claims 3-4 require that cells of the packaging cell line contain substantially more mitochondria and/or more reactive oxygen species (ROS) per cell than cells from the starting cell line and cells from the packaging cell line have a level of staining that is at least 1.5-fold higher than cells from the starting cell line.
Based on the description above, Kondo et al. teaches the fused CHO cell lines produce higher protein such as GFP (See Fig. 3 above and page 1123), and does not explicitly point out selecting cells based on the staining of mitochondria and/or more reactive oxygen species (ROS) in cells. However, Kondo et al. teaches the same active steps of fusing CHO cells to produce the hybrid cells as claimed, thus the fused CHO cells of Kondo will have the same properties of claims 3, 4 and 16 (i.e., more mitochondria and/or more reactive oxygen species (ROS) than the starting cells has as claimed, where including the using of a dye to stain cells to show the higher-level staining in the fusion cells than the starting cells).
(Previous rejection- maintained) Claims 11 is rejected under 35 U.S.C. 103 as being unpatentable over Kondo et al. (2004 Nov;35(5):1120-6) as evidenced by Li et al. (Electron J Biotechnol. 2019 Sep; 41:56-59) as applied to claims 1, 6-7, 9-10, 13 and 20 above, and in view of Vasireddy et al. (PLoS One. 2015 Jun 19;10(6): e0129982).
Claim 11 requires the expression of the nucleic acid payload in a human subject in vivo upon administration to a subject in need.
Based on the description above, Kondo and Li teach the fused CHO cell lines produce higher protein such as GFP and GPL-1 Fc. However, it is silent on an administration to a human subject.
Vasireddy et al. describes the AAV-Mediated Gene Therapy for Choroideremia: Preclinical Studies in Personalized Models. Vasireddy et al. teaches that Choroideremia (CHM) is an X- linked retinal degeneration that is symptomatic in the 1st or 2nd decade of life causing nyctalopia and loss of peripheral vision. CHM is a favorable target for gene augmentation therapy, as the disease is due to loss of function of a protein necessary for retinal cell health, Rab Escort Protein 1 (REP1).The CHM cDNA can be packaged in recombinant adeno-associated virus (rAAV), which has an established track record in human gene therapy studies. Delivery of the CHM cDNA to affected cells restores REP1 enzymatic activity and also restores proper protein trafficking. The gene transfer is efficient and the preliminary safety data are encouraging. These studies pave the way for a human clinical trial of gene therapy for CHM (See Abstract).
Vasireddy et al. teaches the method for Generation of a Recombinant Adeno-associated Virus (AAV) Carrying the Full-length Human REP-1-encoding cDNA and transfecting the AAV vector into CHO cell line using Lipofectamine 2000 and Fugene-6 transfection reagent (See page 2, right column). Vasireddy et al. also teaches the Safety of Infection with AAV2.hCHM in vitro and in vivo by administrating AAV2. hCHM to wild type (C57Bl/6) mice, where the results of subretinal delivery of AAV2. hCHM show that transfer of the REP-1-encoding gene to retinal cells results in high levels of expression without significant evidence of toxicity. Vasireddy et al. discloses that the pAAV2.CBAe.hCHM construct will also be used to generate a clinical vector to be used in human clinical trials (See Competing Interests), which indicates a administration in human based on the needs as claimed.
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to apply the AAV-based therapy into Kondo’s system to arrive at an invention as claimed. One of skill in the art would have been motivated to do so to express the AAV2. hCHM in Kondo’s system to test a possible better system for producing AAV2. hCHM in order to treat Choroideremia or other human disease. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated and commonly used as evidenced by the prior art teachings.
(New rejection) Claims 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Kondo et al. (2004 Nov;35(5):1120-6) as evidenced by Li et al. (Electron J Biotechnol. 2019 Sep; 41:56-59) as applied to claims 1, 6-7, 9-10, 13 and 20 above, and in view of Liu et al. (US 8,703,480 B1, Patented on Apr. 22, 2014).
Claims 21-22 requires the viral vector or particle is an adeno-associated virus (AAV) or a lentivirus (LV) vector or particle.
Based on the description above, Kondo et al. teaches the hybrid CHO cell lines producing higher retroviral particles of MLV. However, Kondo does not explicitly point out the virus can be a AAV or lentivirus.
Liu et al. teaches a Hybrid Packaging Cells providing for efficient propagation of virus vectors, where the hybrid cells are derived from two cells (See column 26, lines 40-64) such as NIH 3T3, U937, H9 or 293 (See claim 8, column 56) and contains the genetic information for the production of the gag, pol and env sequences necessary for production of a virus particle as well as sequences for a selectable marker (See column 27, lines25-35). The viral vector or particle produced in the hybrid cells are AAV Vector Viruses from a heterologous vector retrovirus inactivated for ppt function and containing non-native vector components derived from AAV (See Example 8, column 40). Liu et al. further teaches that the heterologous vector retrovirus, incorporating into the retrovirus nucleic acid component of two such ITR sequences, can provide independent capabilities for the efficient propagation of said vector viruses in packaging cells and for the efficient gene delivery to target cells. Affinity for the packaging cell provides for propagation to high yields by the ability of propagated vector viruses to re-infect packaging cells and undergo repeated cycles of propagation (See column 17, lines 40-50; Column 18, lines 22-48).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings from Kondo and Liu to develop a hybrid cell line expressing heterologous vector (retrovirus vector) DNA construct containing two AAV ITR sequences that flank the primer binding site (See Fig. 10, Liu et al.). One of skill in the art would have been motivated to do so based on the advantage as described above, and there would have been a reasonable expectation of success to arrive at an invention as claimed in the instant application.
Responses to Applicant’s Remarks
Applicant’s arguments filed on May 13, 2025 and July 1, 2025 have been received and fully considered.
The amendment of the drawings dated 7/21/2025 has been considered and accepted.
Applicant’s arguments on the rejections under 35 U.S.C. § 112(a) is not fund persuasive.
The applicant argued that the “specification provides sufficient representative examples to support the use of mammalian cells as a genus. In terms of virus production, all mammalian cells work essentially the same way, and the completed capsids are released by exocytosis or cell lysis. A virus will use the same molecular biology and the same subcellular assembly pathways in any mammalian cell that it is using as host” with an example for AAV genome replication in the cells (See page 6, Remarks, May 13, 2025; page 8, Remarks, July 21, 2025). This argument is not persuasive because not every packaging cell line can support AAV replication. Also, not every mammalian cell line can become a packaging cell line, and not every type of virus vector/particles can be produced in any packaging cell line. It is a written description rejection on the generic claims in the instant application. The data of Fig. 10 regarding the AAV production in the hybrid cells does not meet the requirement for representing the full scope of claims.
3. Applicant’s argument on the rejection under 35 USC § 103 is not fund persuasive as follows:
1). The argument on Fig. 3 (See pages 7-8, Remarks, May 13, 2025; page 7, Remarks, July 21, 2025) is not persuasive.
Fig. 3, luciferase activity was significantly elevated 24 h after co-culturing CHOmcat and CHOpac cells, suggesting that fusion had occurred between these two types of cells (See Kondo et al., page 1122, right column, paragraph 1). Therefore, the level of the GFP activity as a reporter gene represents the level of the production from the hybrid cells. In addition, the instant specification discloses that “Functional titer can be measured by cell transduction using a fluorescent or chemiluminescent protein as a reporter” (See Instant specification, e.g., [0136]).
2). Kondo’s paragraph (See Kondo et al., page 1122, right column, paragraph 1) referred by the applicant further demonstrats that the infectious retroviral particles at ~ 175 cfu/ml are produced by the co-culture supernatants of CHOmcat and CHOpac, where fusion occurred between these two cell lines but not with others, which teaches that the hybrid cells produce higher viral particles than the parental cell lines.
3). Applicant’s argument on “in all likelihood, the final cells are no better than the starting cells in this respect, because they have not been deliberately sorted for either mitochondria phenotype or virus productivity” (See page 8, Remarks, July 21, 2025) is not persuasive. Kondo et al. teaches generating a hybrid cell line and produce higher viral particles, where the start CHO cell line is able to produce viral particle itself as well. As for the sorting for either mitochondria phenotype or virus productivity to select the hybrid cells argued in the page 8 of Remarks, the base claim 1 does not require the limitation for phenotype sorting the hybrids by mitochondria. At the same time, Kondo’s teaching demonstrates the selection for the higher viral production fusion cells generated by CHOmcat cells and CHOpac cells. Also, the new cited art of Liu et al. also teaches the hybrid packaging cells that can provide for efficient propagation for viral vectors (See column 26, lines 40-67, Liu et al.)
In addition, the parental cells, hybrid cells and the reporter marker in Kondo possess the similar features and genetic elements as claimed, therefore, the acquired function of the hybrid cells of Kondo should be comparable with the function of the hybrid cell as claimed in the instant application.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RUIXUE WANG whose telephone number is (571)272-7960. The examiner can normally be reached Monday-Friday 8:00 am..
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/RUIXUE WANG/Examiner, Art Unit 1671
/NICOLE KINSEY WHITE/Primary Examiner, Art Unit 1671