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 .
Detailed Action
Election/Restrictions
Applicant's election with traverse of the following species in the reply filed on 03/23/2026 is acknowledged.
Protein expression regulation: increase protein expression
Method of regulation: introducing an exogenous plasmid into the cell.
A protein derived from the cell: NOVA2
Applicant traverses the restriction and argues “The Office has not
provided any reasons or examples to support a conclusion that the species are indeed patentably distinct”, citing MPEP 808.01(a).
The reasons for search burden, as stated in the previous action filed 01/23/2026 are restated below:
The alternatives of species 1-3 are not regarded as being of similar nature because: (1) the alternatives do not all share a common structure and (2) the alternatives do not all belong to a recognized class of chemical compounds.
The alternatives each behave in a different way in the context of the claimed invention. Each member of the class cannot be substituted, one for the other, with the expectation that the same intended result would be achieved.
Because Applicant do not refute the statement of burden with a specific argument directed to the statement of burden the restriction requirement is deemed proper and therefore made FINAL.
Priority
The present application is a CON national stage filing of International Application No. JP2020-217338, filed 12/25/2020.
Applicant' s claim for the benefit of a prior-filed parent provisional application 18340593, filed on 12/23/2021, under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55 for the Foreign Priority Application, filed 10/03/2023.
The effective priority for the instant application is 12/23/2021.
Claims Status
No claims are canceled, no claims are newly added, claims 7-10, 20-23, 31-32 and 36-37 have been withdrawn from consideration as being drawn to non-elected subject matter, and claims 1-6, 11-19, 24-29 and 33-35 have been considered on the merits.
Claim Objections
Claim 12 is objected to because of the following informalities: The claim recites “the aforementioned human cell is HEK293 cell”. If the claim were amended to recite “the aforementioned human cell is a HEK293 cell” the grammar of the claim would be correct.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-4, 6, 11, 13 are rejected under 35 U.S.C. 101 because the claimed inventions are directed to a judicial exception (specifically a natural product) without significantly more.
The claims have been analyzed for eligibility in accordance with their broadest reasonable interpretation.
Regarding claims 1 and 11: Claim 1 is drawn to a product (in this case the viral vector-producing cell is considered a product).
While the claim requires the cell to be capable of producing a viral vector, a viral vector is not required by the claim.
Thus the broadest reasonable interpretation of “a viral vector-producing cell” is any cell which is capable of producing viral vectors.
The claim recites “with an improved ability to produce vectors”. The intended use statement “with an improved ability to produce vectors” does not impose or imply a structural limitation to the claimed product. The claimed product is therefore interpreted as “a viral vector-producing cell” in the following claim analysis.
The claim recites “wherein expression of a protein derived from the viral vector-producing cell in the cell is regulated”. This limitation is extremely broad and encompasses any protein that is expressed within a cell because expression of a protein is regulated.
Therefore the broadest reasonable interpretation of the claim is any cell which can produce any viral vector and expresses any protein.
Step 1: Is claim directed to a statutory category of invention?
Yes, the claim is drawn to a product (a viral vector-producing cell), which is a statutory category of invention (Step 1: YES).
Step 2A, Prong 1: Does the claim recite a product of nature judicial exception (JE)?
The scope of the claimed cell is broad and encompasses any cell in the human body that can be infected by a virus.
Therefore the claimed viral vector-producing cell is identical to naturally occurring viral vector producing cells because there is no marked difference between the claim and product of nature; a naturally occurring eukaryotic cell which can be infected by a virus.
Thus the claim does recite a product of nature judicial exception (Step 2A, Prong 1: YES).
Step 2A, Prong 2: Does the claim recite additional elements that integrate the JE into a practical application?
The claim does not integrate the product into a practical application because the claim is to the viral vector-producing cell, per se, not a method of use. (Step 2A, Prong 2: NO).
Step 2B: Are there additional elements that add significantly more to the ‘product of nature judicial exception' ?
Claims 1 and 11 do not recite any elements in addition to the viral vector-producing cell, so there are no additional elements that add significantly more to the judicial exception.
Claim 2 recites “expression of the protein derived from the viral vector-producing cell is regulated as compared with that in the viral vector-producing cell before regulation of the expression of the aforementioned protein”.
The phrase “the expression of the protein… is regulated as compared with that… before regulation” does not impart or imply structure to the claimed cell, therefore so there are no additional elements that add significantly more to the judicial exception.
Claims 3 and 4 require the protein expression to be increased at least 1.5 times at the time of viral production, as compared to before regulation of the protein.
Therefore there are no additional elements that add significantly more to the judicial exception.
Regarding claim 6: the claim requires the expression of the protein NOVA2 to be increased in the cell. NOVA2 is an endogenous human protein that is naturally expressed, and expression is regulated. Thus increased expression of NOVA2 does not differentiate the claimed cell from a naturally occurring cell.
Therefore there are no additional elements that add significantly more to the judicial exception.
(Step 2B: NO).
The claims are patent ineligible.
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.
Claims 1-5, 11-13, 14-18, 24-29, and 33-35 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.
Regarding claim 1: The claim is drawn to a product, a viral vector-producing cell.
While the claim requires the cell to be capable of producing a viral vector, a viral vector is not required by the claim.
Thus the broadest reasonable interpretation of “a viral vector-producing cell” is any cell which is capable of producing viral vectors.
The claim recites “with an improved ability to produce vectors”. The intended use statement “with an improved ability to produce vectors” does not impose or imply a structural limitation to the claimed product. The claimed product is therefore interpreted as “a viral vector-producing cell” in the following claim analysis.
The claim recites “wherein expression of a protein derived from the viral vector-producing cell in the cell is regulated”. This limitation is extremely broad and encompasses any protein that is expressed within a cell because expression of a protein is regulated.
Therefore the broadest reasonable interpretation of the claim is any cell which can produce any viral vectors and expresses any protein.
Teachings of the instant specification:
The instant specification teaches HEK293 cells that are transfected with plasmids encoding AAV2 proteins to produce viral vectors (Example 1; p37). The specification further teach host cell-derived proteins were extracted and proteins that showed 1.5 times or more variation in expression in virus producing cells were identified (Tables 1 and 2).
The specification further teach 14 proteins (PIK3C2A, UBE2C, ASNS, NIFK, PDCD4, DDX47, GTPBP4, FTSJ3, DDX49, GNL2, NATl0, UBL5, SERBPl, and
NOVA2) were transiently expressed in the production cell (Example 2; p42 ln 4-10).
The specification further teaches improved AAV production for the 14 proteins that were transiently expressed in the production cell (Fig 1-6; ln25-30)
The specification teach 5 proteins (MREll, ISG15, CD44, LMNA and ACP2) were knocked down in the production cell (Example 3; Table 5; p45 ln10-15).
The specification further teaches improved AAV production for the 5 proteins that were knocked down (Fig 7-11; p51 ln26-30).
The state of the art:
Hitchcock et al (BioProcess International (2017) p2-12) teach AAV vector production has well known shortfalls and new platforms to generate scalable and cost-effective platforms are needed (p2 ¶2). Hitchcock teach heterogeneity with AAV vectors, resulting in full, empty and incomplete capsids are challenges for producing a licensed product (p3 ¶1). Hitchcock further teach the processes for virus assembly within a cell are only understood at a high level, particularly for factors that affect assembly and packaging efficiency, and thus product developers must take an empirical approach to identify factors affecting factors affecting vector heterogeneity and key steps to control it (p3 ¶4).
Conclusion:
The instant specification provides working examples of a single producer cell (HEK293) and 14 proteins which are upregulated and 5 proteins which are downregulated.
The instant specification does not provide sufficient guidance or working examples of the broad genus of viral vector-producing cell as claimed, which could be any cell with any protein regulated and any virus produced.
As discussed, Hitchcock processes to improve viral production must be tested empirically.
Therefore trial and error experimentation is required to test how changes to a specific protein effects AAV production, and the effect of such changes cannot be predicted.
MPEP 2163 states “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”.
As described above, the claimed invention is broad and includes any cell that expresses any protein and can produce any virus.
In view of the unpredictability in predicting factors that can improve AAV production, as taught by Hitchcock, and the trial and error necessary for the identification and effective use of such factors, the specification fails to support the broad genus of “a viral vector-producing cell” as claimed such that one skilled in the art can reasonably conclude the inventor had possession of the claimed invention.
The gap between the limited number of structures corresponding to those that exhibit an improved ability to produce vectors as described in the specification compared to the breadth any viral vector-producing cell is extremely large. Given this large gap, the specification fails to support the broad genus of “viral vector-producing cell” as claimed such that one skilled in the art can reasonably conclude the inventor had possession of the claimed invention.
Note that claims 1-5, 11-13, 14-18, 24-29 and 33-35 and fail to cure the deficiency.
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 1-6, 11-19, 24-29 and 33-35 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.
Claims 2-4, 15-16, 28-29, 34 and 35: As discussed supra, the claims recite and Accession number in reference to the HEK293 cell. It is not clear if the Accession number is an example of a preferred cell type or if it is required by the claim. For purposes of compact prosecution the Accession number is considered exemplary.
Regarding claims 1, 14, 33: The term “improved ability” in the is a relative term which renders the claims indefinite. The term “improved ability” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Note claims 2-6, 11-19, 24-29 and 33-35 depend from claim 1 and do not cure the deficiency.
Regarding claim 2: The claim recites “expression of the protein derived from the viral vector-producing cell is regulated as compared with that in the viral vector-producing cell before regulation of the expression
of the aforementioned protein”.
The phrase “the expression of the protein… is regulated as compared with that… before regulation”
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1-5, 11-18, 24-29 and 33-35 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Farris et al (Human Gene Therapy (2008) 19;1421-1427).
Regarding claim 1: Claim 1 recites a viral vector-producing cell. The instant specification defines “viral vector” as a vector in which a naturally occurring virus is modified using genetic recombination technology to permit the transfer of a desired gene or the like into the target” (p1 ln 30-35).
However, while the claim requires the cell to be capable of producing a viral vector, it is noted that a viral vector is not required by the claim. Thus any cell which is capable of producing a viral vector is considered to read on “a viral vector-producing cell”.
The claim recites “with an improved ability to produce vectors”. The intended use statement “with an improved ability to produce vectors” does not impose or imply a structural limitation to the claimed product. The claimed product is therefore interpreted as “a viral vector-producing cell” in the following claim analysis.
MPEP (2111.02 II) states “During examination, statements in the preamble reciting the purpose or intended use of the claimed invention must be evaluated to determine whether or not the recited purpose or intended use results in a structural difference (or, in the case of process claims, manipulative difference) between the claimed invention and the prior art. If so, the recitation serves to limit the claim”.
The claim recites “wherein expression of a protein derived from the viral vector-producing cell in the cell is regulated”. This limitation is extremely broad and encompasses every protein that is expressed within a cell because expression of every protein produced in a is regulated, in order for a protein to be expressed transcription and translation must be activated.
The claim recites “a protein derived” from the cell. The instant specification is silent on an explicit definition of the term “derived”. As evidenced by Dictionary.com, “derived” means “received, obtained, or arising from a particular source or in a particular way” (https://www.dictionary.com/browse/derived). Thus the broadest reasonable interpretation of a protein derived from a cell is a protein obtained or arising from the cell and encompasses any protein of any origin that is expressed by the producer cell.
Therefore the broadest reasonable interpretation of claim 1 is a cell which can produce viral vectors and expresses a protein.
Claim 5 requires the addition of an additive or an exogenous plasmid to the cells. Because Applicant elected “an exogenous plasmid” the “addition of an additive” is not examined in the instant analysis.
Farris teach a viral vector producing cell; for rAAV production cells (human HEK 293T cells) were plated onto 100-mm dishes the day before transfection (p1422 col1 ¶5). The 293T cells are transfected with AAV vectors supplying packaging elements (pMU2) Rep proteins (RepSM) and helper functions (pHelper) (p1422 col2 ¶2). This reads on claim 1; a viral vector-producing with an improved ability to produce vectors because the transfected cells of Farris have an improved ability to produce vectors compared to cells that are not transfected.
The teachings of Farris also read on an exogenous plasmid (AAV vectors supplying packaging elements, Rep proteins and pHelper), as required by claim 5.
Regarding claim 2: The claim recites “expression of the protein derived from the viral vector-producing cell is regulated as compared with that in the viral vector-producing cell before regulation of the expression
of the aforementioned protein”.
The phrase “the expression of the protein… is regulated as compared with that… before regulation” does not impart or imply structure to the claimed cell.
Regarding claim 3: The teachings of Farris are discussed supra. As discussed supra, any protein produced by the cell is considered derived from the cell. Thus the cells of Farris which are transfected with plasmids to generate AAV are considered to read on “a protein derived from the viral vector producing cell is increased” compared to cells that are not transfected with plasmids to generate AAV.
Regarding claim 4: The teachings of Farris are discussed supra. The transfected 293T cells taught by Farris produces viral proteins. These proteins are considered derived from the cell because the cell generates the proteins.
Because cells do not generate produce AAV before they are transfected with plasmids to generate AAV, the transfected cells of Ferris read on expression of a protein derived from the viral vector-producing cell at an increase of 1.5 times or more than before regulation of the expression (before infection).
Regarding claim 13 and 26: The teachings of Farris are discussed supra. As discussed above, while the invention requires a cell capable of producing viral vectors, the claims do not require a viral vector. Thus the adeno-associated viral vector recited does not imply or impart structure on the claimed cell.
Regarding claims 14-15, 18, 24, 26-29: The claim recites a method for making a cell “with an improved ability to produce vectors”.
The viral vector producing cells with an improved ability to produce vectors is considered a product of the claimed process and is considered an intended result which would be obtained by any method which comprises the active steps and required structures of the claimed method.
The active step recited by the claim is “regulating expression of a protein derived from the viral vector-producing cell”.
As discussed supra, a protein derived from the viral vector-producing cell is considered extremely broad and encompasses any protein that is expressed within a cell because expression of a protein in a cell activation of expression.
The structure required by the claim is a cell which can produce a viral vector. It is noted that a viral vector is not required by the claimed method.
Farris teach a viral vector producing cell; for rAAV production cells (human 293T cells) were plated onto 100-mm dishes the day before transfection (p1422 col1 ¶5). The 293T cells are transfected with AAV vectors supplying packaging elements (pMU2) Rep proteins (RepSM) and helper functions (pHelpler) (p1422 col2 ¶2). This reads on an exogenous plasmid, as required by claim 5.
While “an improved ability to produce vectors” is considered a result of the structure of the cells and does not impart or imply structure on the vector-producing cells, the transfected 293T cells are considered to have an improved ability to produce vectors compared to 293T cells that are not transfected.
Transfecting the cells is considered to read on “regulating” expression of a protein derived from the viral vector-producing cell because expression enables increased expression of the encoded proteins in order to generate AAVs.
Regarding claims 16-17: The teachings of Farris are discussed supra.
Because viral capsid proteins are expressed in the transfected cells, but not expressed in the cells before transfection, the cells of Farris read on an increase of protein expression 1.5 for more.
Regarding claim 33-35: The teachings of Farris are discussed supra. Farris teach the cells are transfected with pMU2, which contains a GFP-encoding gene as a reporter gene, as described by Reed et al (p1422 col1 ¶2).
Farris teach that sixty hours posttransfection, cells were collected and processed (p1422 col2 ¶6). Collecting the cells that have been transfected is considered selecting the cells in which the expression of a protein is regulated, as required by the claim.
Transfecting the cells is considered to read on “regulating” expression of a protein derived from the viral vector-producing cell because expression enables increased expression of the encoded proteins in order to generate AAVs.
Therefore the invention as claimed is anticipated by Farris et al.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 6 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Farris et al as applied to claims 1-5, 11-13, 16-17, 26 and 33-35 above, and further in view of Trempe et al (Journal of Virology (1988) 62:9;1-8), Chen et al (Nat Rev Mol Cell Biol (2009) 10:11;1-27), Yano et al (Neuron (2010) 66:6;1-20).
Claims 1-5, 11-18, 24-29 and 33-35 are anticipated by Farris et al, and thus are also rendered obvious (see above).
Regarding claims 6 and 19: The teachings of Farris are discussed above.
Farris teach AAV capsid proteins are thought to be a rate-limiting step in the production of recombinant AAV (Abstract). Recombinant AAV is considered a viral vector. Farris further teach that the three capsid proteins of AAV are primarily generated from spliced mRNAs (p1421 col2 ¶2). Farris further teach that an enhancement of splicing levels of the capsid-generating pre-mRNA transcripts results in proportional increases in rAAV vector production (p1422 col1 ¶2). Ferris teach for AAV1 and AAV2, improved donor sites resulted in 6-7 fold and 2-fold increases in in splicing and proportional increases in capsid protein production (p1424 col1/2 ¶2/1).
While Farris teach improving AAV production by improving splicing levels by generating AAV RepCap vectors with improved nonconsensus donor sites (p1424 col1 ¶2), Farris do not teach improving AAV production by improving splicing levels by delivering NOVA2 to the cells.
Trempe teach synthesis of VP1 for AAV requires alternative splicing (p1 col2 ¶2).
Chen teach alternative splicing is a mechanism for gene regulation and generating proteomic diversity (p1 ¶1). Chen further teach then intronic splicing enhancers hnRNP F, hnRNP H, NPVA1, NOVA2, FOX1 and FOX2 bind intronic splicing enhancers and stimulate splicing (p2 ¶1).
Yano teach protein-RNA interactions have critical rolls in all aspects of gene expression and generate genome-wide mapping of the NOVA/RNA binding (abstract). Yano teach high-throughput sequencing methods to map NOVA-RNA interactions in vivo (p1 col1 ¶3). Yano also teach transfection of NOVA2-expressing plasmids into 293T cells (p7 col2 ¶6).
It would have been obvious to one of ordinary skill in the art to modify the viral vector-producing cell of Farris drawn to a cell transfected with plasmids to generate AAV virus which has increased efficiency of alternative splicing using improved non-consensus donor sites with the teachings of Yano, to transfect the cells with NOVA2-expressing plasmids.
One of ordinary skill in the art would have been motivated to modify the viral vector-producing cell taught by Farris by transfecting NOVA2-expressing plasmids into the cells, as taught by Yano, because Chen teach NOVA2 stimulates splicing and Trempe teach synthesis of the AAV1 capsid protein VP1 requires alternative splicing.
One would have had a reasonable expectation of success because the inventions are drawn methods of manipulating protein expression in 293 cells using well understood molecular biology methods.
Thus the invention as claimed is rendered obvious by the teachings of Farris et al in view of Trempe et al, Chen et al and Yarro et al.
Conclusion
No claims are allowed.
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/ANDREA LYNNE MORRIS SPENCER/Examiner, Art Unit 1631
/TAEYOON KIM/Primary Examiner, Art Unit 1631
