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 .
Response to Amendment
The amendment filed 07/28/2026, amending claim(s) 1, 7, 9-11, 13 and cancelling claim(s) 6 is acknowledged.
Applicant’s amendments to the claims have overcome the 112(a) written description rejection regarding the phrase “reversely inserted gene expression cassette” and 112b rejections previously set forth in the Non-Final Office Action mailed 04/29/2026.
Claims 1-5 and 7-16 are pending.
Claims 3, 15, and 16 remain withdrawn.
Claims 1, 2, 4, 5, and 7-14 are pending and under examination.
Incorrect Claim Status
The amendment to the claims filed on 07/28/2026 does not comply with the requirements of 37 CFR 1.121(c). Amendments to the claims filed on or after July 30, 2003 must comply with 37 CFR 1.121(c) which states:
(c) Claims. Amendments to a claim must be made by rewriting the entire claim with all changes (e.g., additions and deletions) as indicated in this subsection, except when the claim is being canceled. Each amendment document that includes a change to an existing claim, cancellation of an existing claim or addition of a new claim, must include a complete listing of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims, in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).
The correct status of claim 16 is (withdrawn).
Priority
Applicant’s claim for the benefit to CN202011418514.0 filed 12/07/2020 and PCT/CN2021/135790 filed 12/06/2021 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Applicant’s English translation of the certified copy of CN202011418514.0 and statement that the translation of the certified copy is accurate filed on 07/28/2026 is acknowledged.
Drawings
The replacement drawings filed 07/28/2026 are accepted.
Specification
The specification filed 06/07/2023 is accepted.
Claim Rejections - 35 USC § 112(a) – Written Description –Maintained, incorporating amendments
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, 2, 4, 5, and 7-14 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.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
Claim 1 recites “the repressible operon is configured to repress expression of the gene of interest downstream of the repressible operon in the presence of a repressor.”
Claim 1 recites “wherein the gene of interest is a gene that exerts a negative effect on viral packaging in the case where the gene of interest is expressed”.
Claim 7 recites “wherein the gene of interest is a gene that has cytotoxicity to cells for lentiviral packaging.”
Claim 10 recites “wherein the gene of interest is a gene that directly inhibits replication and/or assembly of virus.”
Claim 13 recites “wherein the lentiviral vector packaging system is configured to produce HIV vector particles having only primary infectivity and no replication capacity.”
Either these are inherent properties of (that naturally flows from) the structure of claim 1, or they are not.
The claim denotes that not all of the structures/method steps of the independent claim are able to achieve the functional property(ies) recited in the dependent claim(s).
To the extent it is not an inherent property (that naturally flows) from the product/method of the independent claim, then something must change. The claim is considered to lack adequate written description for failing to recite the structure that is necessary and sufficient to cause the repressible operon, gene of interest, and vector to possess these characteristics. The claim limitations recited above merely state functional characteristics without providing any indication about how the characteristic is provided. The characteristic does not follow from (is not an inherent property of) the structure recited in the claim, so it is unclear whether the claim requires some other structure to be added to the composition to provide the characteristic.
The specification fails to disclose what structural changes (e.g., configurations) to the composition is/are necessary and sufficient to cause the recited function of repressing expression of the gene of interest downstream of the repressible operon in the presence of a repressor, for example, and thus the ordinary artisan would not know what modification(s) must be made in order to fulfill the instant recitation. For example, how would an artisan know what configurations of the repressible operon do/do not result in the operon repressing expression of the gene of interest downstream of the repressible operon in the presence of a repressor? Or what genes of interest have cytotoxicity to cells for lentiviral packaging, versus what genes of interest do not have cytotoxicity to cells for lentiviral packaging?
The claims fail to recite, and the specification fails to disclose what modification(s) to a lentiviral vector packaging system that is unable to produce HIV vector particles having only primary infectivity and no replication capacity, transforms said lentiviral vector packaging system into one that is now necessarily and predictably capable of producing HIV vector particles having only primary infectivity and no replication capacity, for example (e.g., what structural configuration results in the recited function?).
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function…does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Stanford (US20210024924A1, published 01/28/2021; originally filed 03/04/2020) is considered relevant prior art for teaching a vector comprising a 5’ long terminal repeat (LTR), gene expression cassette comprising a repressible operon and promoter, and a 3’ LTR (i.e., the same structure recited in base claim 1). However, Stanford is silent on the functionality of the gene of interest (as part of a lentiviral packaging system) exerting a negative effect on viral packaging in the case where the gene of interest is expressed, and does not provide any further guidance on what structure of the gene of interest would cause this functionality. Instead, the functionality of the gene(s) of interest and vector(s) for genetic engineering to treat diseases such as Huntington’s Disease (e.g., when targeting CASP2) [0281] are instead described.
Liu (www.genscript.com/learning-center/lentivirus-the-ultimate-answer-for-efficient-gene-delivery.html; published 04/21/2025) is considered relevant art for providing an overview of lentiviruses. Liu teaches that lentiviruses are derived from HIV-1, and that through genetic engineering, regulatory and auxiliary genes necessary required for viral replication are removed, and heterologous elements are introduced to create a replication-deficient recombinant vector system.
Liu does not provide further guidance on how an artisan would possess a vector for lentiviral packaging comprising LTRs and a gene expression cassette/a lentiviral vector packaging system comprising said vector that would also produce HIV vector particles with replication capacity. Instead, Liu teaches that it is known in the art that lentiviruses do not have replication capacity.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph, and the Artisan would not have understood Applicant to have been in possession of the invention as claimed.
Claim Rejections - 35 USC § 102/103 - Maintained, incorporating amendments
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1, 2, 5, and 7-14 is/are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Stanford (US20210024924A1, published 01/28/2021; originally filed 03/04/2020).
Regarding claim 1, Stanford teaches a lentiviral plasmid that is integrated into HEK 293T cells to generate a reporter cell line, HEK293T QMS (CMVS-CuO luc-p2A-GFP, EF1alpha-cymR). This teaching reads on the claim language of instant claim 1 (a vector for lentivirus comprising a first long terminal repeat (LTR), a gene expression cassette comprising a repressible operon and promoter, and a second long terminal repeat, wherein the first LTR is upstream (5’) of the expression cassette, and the second LTR is downstream of the expression cassette) [0129] (Fig. 10- included below).
As discussed in the 112(a) written description rejection above, the recitations of “wherein the gene of interest is a gene that exerts a negative effect on viral packaging in the case where the gene of interest is expressed” and “the repressible operon is configured to repress expression of the gene of interest downstream of the repressible operon in the presence of a repressor” these are functional properties that do not further limit the structure of the claimed vector. Specifically, the recitation “is configured” does not further define the structure of the claimed invention (e.g., the claim language is still describing the repressible operon in the vector functionally rather than structurally). As such, absent evidence to the contrary, the structure taught by Stanford would inherently be able to carry out functions such as exerting a negative effect on viral packaging and producing HIV vector particles having only primary infectivity and no replication capacity (claim 13).
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Further, the vector taught by Stanford above (Fig. 10) comprises GFP as a gene of interest. However, Stanford teaches that the gene of interest in a vector may be a gene associated with neoplasia, such as those in the caspase family, including CASP2 [0280].
It would have been obvious to one of ordinary skill in the art to substitute CASP2 for luciferase/GFP as the gene of interest in the vector taught by Stanford and arrive at the claimed invention. One would have a reasonable expectation of success because Stanford suggests such modification, and it is routine in the art to substitute the gene present in a gene expression cassette depending on the motivation of the artisan. An artisan would be motivated to make this substitution because as taught by Stanford, the CASP2 gene is associated with cellular performance, and the disclosed editing system may be used to treat diseases associated with cellular condition, such as those associated with disrupted CASP2 (Stanford notes that CASP2 is specifically associated with Huntington’s Diseases signaling, apoptosis signaling, death receptor signaling) [0281].
Regarding claim 2, Stanford teaches the repressible operon being a Cumate-CuO regulable system (Fig. 10).
Regarding claim 5, Stanford teaches the promoter being CMV (Fig. 10).
Additionally, regarding claims 7 and 10, as discussed in the 112(a) written description rejection above, these are functional properties that do not further limit the structure of the claimed vector/gene. As such, absent evidence to the contrary, the structure taught by Stanford would inherently be able to carry out functions such as having cytotoxicity to cells for lentiviral packaging. Further, the Applicant notes that CASP2 possesses the functional properties as described in the claims (see Applicant’s response to restriction, page 2).
Regarding claim 12, the vector taught by Stanford further comprises an enhancer (e.g., WPRE) (Fig. 10).
Regarding claim 14, Stanford teaches the lentiviral vector packaging system being a three-plasmid packaging system, e.g., [0374-0377], [0397-0398].
Claim(s) 1, 2, 4, 5, and 7-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stanford as applied to claims 1, 2, 5, and 7-14 above, and further in view of Massie et al. (US20040205834A1, published 10/14/2004).
As shown above, the base claims are obvious over the base art.
Stanford is silent on the distance of a CuO element inserted into a gene expression cassette and a TATA box of the promoter. However, Stanford teaches the vector comprising a CMV promoter, the same promoter present in the vectors disclosed in the instant specification, which are noted to possess a TATA box (see [0023] and Fig. 15 of instant specification).
An Artisan, interested in the Cumate-CuO regulable system, would be aware of Massie et al. for teaching a Cumate-inducible expression system for eukaryotic cells.
Massie et al. teaches an engineered vector virus comprising a) a mammalian promoter sequence (such as CMV) having a TATA element; b) at least one CymR operator sequence positioned 3′ to the TATA element; and c) a gene, such as for example a transactivator, lying 3′ to said operator and operably linked to said promoter (claims 13 and 14 of Massie et al.). In Massie et al., operator sequences are placed further away from the TATA box (19 or 40 bases from the TATA) [0122].
It would have been obvious to one of ordinary skill in the art to modify the vector disclosed by Stanford by placing the CuO element 40 nucleotides from a TATA box of the promoter as taught by Massie et al. and arrive at the claimed invention. One would have a reasonable expectation of success because both Stanford and Massie utilize the CMV promoter. An artisan would be motivated to make this modification because as taught by Massie et al., the operator sequences placed further away from the TATA box (e.g., 40 bases from the TATA) are able to mediate repression by the repressor very effectively. Further, Massie et al. notes that the positioning of the operator site should not be restricted to specific sites, as other sites may be found acceptable by one skilled in the art by simple routine testing [0122].
Response to Arguments
Applicant's arguments filed 07/28/2026 have been fully considered but they are not persuasive.
First, the Examiner notes that the amendments to claims 1 and 13 changing “capable of” to “configured to” and amendments to claims 7 and 10 adding the gene of interest “is a gene” do not remedy the deficiencies described in the 112(a) written description rejections above (e.g., they do not change the claim interpretation).
Regarding the 112(a) written description rejection, Applicant argues “the specification expressly defines "negative effect on viral packaging" (reducing packaging efficiency, slowing or hindering virus release, directly killing packaging cells, or occupying cellular resources)”. This argument is not persuasive because the issue is not a lack of understanding of what the recited function is, but in what structure results in/causes the recited function. Knowing that "negative effect on viral packaging" encompasses “reducing packaging efficiency” does not help an artisan determine what gene(s) of interest possess this function.
Further, the Applicant argues “The recitation is not a functional limitation of the vector, but rather a description of the attribute of the gene of interest. Thus, claim 1 defines what type of gene the gene of interest is, rather than what the vector is capable of doing.” Again, this argument is not persuasive because describing the function (e.g., attribute) of a gene doesn’t structurally define the gene. Further, the gene is a part of the claimed vector, so the claim limitations still relate to the functionality of the vector. In kind, the arguments for claims 7 and 10 are not persuasive.
Regarding the 102/103 rejections as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Stanford, the Applicant argues:
“Stanford does not disclose that the gene of interest is a gene that exerts a negative effect on viral packaging. Stanford discloses that the genes of interest are reporter genes that have no negative effect on viral packaging. Stanford merely mentions CASP2 in a lengthy list of candidate therapeutic genes, without any suggestion that CASP2 or any other gene would exert a negative effect on viral packaging. Thus, the "gene of interest" in Stanford is fundamentally different from the "gene of interest" in amended claim 1, which is specifically defined as a gene that exerts a negative effect on viral packaging.”
This argument is not found to be persuasive. As previously stated, the Applicant stated that CASP2 possesses the functional properties as described in the claims (see Applicant’s response to restriction, page 2). Further, the Applicant fails to distinctly point out where or provide evidence to support their assertion that the genes of interest taught in Stanford are reporter genes that have no negative effect on viral packaging.
The Applicant argues:
“Stanford does not disclose or suggest that any gene of interest would exert a negative effect on viral packaging, nor does it recognize the problem that certain genes, when expressed during packaging, reduce viral titer. Viewed from Stanford's use of reporter genes (GFP/luc) that have no negative effect on viral packaging, all of Stanford's working examples were constructed and verified using genes that are harmless to viral packaging. Thus, Stanford teaches that the "CuO system can be used to regulate gene expression". In contrast, the present application teaches that the "CuO system can be used to suppress genes that exert a negative effect on viral packaging." Likewise, when CASP2 is mentioned in paragraph [0280] of Stanford, the context is that CASP2 is a "gene useful for gene therapy" - i.e., a gene that one would wish to have expressed in that context, rather than a gene that exerts a negative effect on viral packaging (one that one would wish not to have expressed during packaging), as required in the present claims. Stanford's working examples and its passing mention of CASP2 are consistent in their context: neither teaches a gene that exerts a negative effect on viral packaging. Therefore, Stanford's listing of CASP2 cannot be viewed as teaching the selection of CASP2 for suppression as a gene that exerts a negative effect on viral packaging. The overall teaching that a person skilled in the art would derive from Stanford remains that the "CuO system can be used to regulate gene expression." Therefore, Stanford fails to provide any motivation to depart from such direction and select genes that exert a negative effect on viral packaging.”
These arguments are not persuasive. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., Stanford does not recognize the problem that certain genes, when expressed during packaging, reduce viral titer) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Additionally, how would an artisan know/determine that all genes used or suggested in Stanford (including CASP2) are “harmless to viral packaging”? The Applicant provides no further evidence in support of this statement.
Further, the Applicant fails to distinctly point out how “regulating gene expression” (as recited in Stanford describing the Cumate-CuO system) does not encompass suppressing genes, as recited in the present application. In addition, the Applicant fails to distinctly point out how the CuO system of Stanford structurally differs from the claimed invention, and why the two system would not possess the same functions.
In response to applicant's argument that when CASP2 is mentioned in paragraph [0280] of Stanford, the context is that CASP2 is a "gene useful for gene therapy" - i.e., a gene that one would wish to have expressed in that context, rather than a gene that exerts a negative effect on viral packaging, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Regarding the 103 rejection of the claims as unpatentable over Stanford further in view of Massie et al., the Applicant argues:
“Massie is directed solely to optimizing the position of the operator element to achieve effective transcriptional repression. Massie does not address lentiviral packaging, does not disclose any gene of interest that exerts a negative effect on viral packaging, and does not suggest using a repressible system to inhibit such genes during packaging to improve viral titer.
Even if one were to combine the teachings of Stanford's lentiviral vector with Massie's teaching on CuO placement, such a combination would at most yield an optimized repressible expression vector for reporter genes. It would not yield the further insight that certain genes are detrimental to viral packaging, nor would it provide the motivation to select such genes for inhibition during packaging. Massie's teaching is limited to "how to place the operator for effective repression".
Therefore, neither Stanford, Massie, nor their combination provides any motivation for a person of skill in the art to select a gene that exerts a negative effect on viral packaging, to recognize that such gene should be inhibited during the packaging phase, or to expect that inhibiting such gene would restore or significantly improve viral titer. Stanford's examples all use reporter genes (GFP, luciferase) that are harmless to packaging cells, and its passing mention of CASP2 in a list of therapeutic genes does not suggest that CASP2 or any other gene has a negative effect on viral packaging. Massie is entirely silent on this issue. Thus, there is no reasonable expectation of success that the combination of Stanford and Massie would solve a packaging problem that neither reference recognized exists.”
These arguments are not found to be persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to applicant's argument that the teachings of Stanford and Massie et al. combined would not yield the further insight that certain genes are detrimental to viral packaging, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Additionally, inhibiting a gene using a repressible operon system such as Cumate-CuO is previously known in the art, as evidenced by the cited references. It would be routine in the art for an artisan to select a gene of interest and to repress said gene depending on their intention/motivation.
The Applicant argues that the present application, in contrast to Stanford and Massie et al., provides experimental evidence demonstrating the advantages of the claimed invention. The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALLISON M JOHNSON whose telephone number is (703)756-1396. The examiner can normally be reached Monday-Friday 9am-5pm.
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ALLISON M. JOHNSON
Examiner
Art Unit 1638
/ALLISON MARIE JOHNSON/ Examiner, Art Unit 1638
/ROBERT M KELLY/ Primary Examiner, Art Unit 1638
