DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 5/13/2026 has been entered.
Election/Restrictions
Applicant’s amendment filed on 4/16/2026 is acknowledged. Claim 10 is canceled.
Applicant’s election without traverse of Invention I, Claims 1-10 and 14-15 in the reply filed on 6/27/2025 is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
Claims 11-13 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6/27/2025.
Claims 1-9 and 14-15 are under examination on the merits.
Response to Arguments
Applicant's arguments, see pp. 1-3, filed 4/16/2026 have been fully considered but they are not persuasive. See below.
A new rejection under 35 U.S.C. §112(a) is raised below.
Maintained Rejections
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 1-9 and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Mineno et al. (WO 2015053398 A1, published 4/16/2015; hereinafter referred to as “Mineno”) in further view of Okamoto et al. (WO 2012157742 A1, published 11/22/2012; hereinafter referred to as “Okamoto”). The rejection of claim 10 is withdrawn due to cancellation of the claim.
Applicant’s arguments have been carefully considered but are found unpersuasive.
Applicant presents the following arguments:
As previously argued, Okamoto et al. teach a vector containing an siRNA expression cassette (i.e., an siRNA-producing sequence) placed at a position different from the present invention (see vector D in FIG. 8 of Okamoto et al.). Okamoto et al. teach that such a vector has a higher expression efficiency of exogenous TCR than a vector containing an siRNA-producing sequence positioned downstream of the TCR coding region (see vector B in FIG. 8 of Okamoto et al. and FIG. 9 and Example 9 of Okamoto et al.).
The combination of Mineno and Okamoto does not provide any hint for selecting the specific position of an siRNA-producing sequence as recited in the claimed invention among various possible positions within the nucleic acid construct.
The combination of Mineno and Okamoto does not suggest that placing an siRNA-producing sequence at the position downstream of a WPRE sequence and upstream of a 3’ LTR produces unexpectedly high gene expression.
One of ordinary skill in the art would arrive at vector B as shown in Figure 1 of the present application, i.e., placing an siRNA-producing sequence between SD/SA sequences. Since vector B would be considered the most effective configuration in view of Mineno and Okamoto, one of ordinary skill in the art would not reasonably expect that the configuration of vector D as shown in Figure 1 of the present application, i.e., placing an siRNA-producing sequence downstream of a posttranscriptional regulatory element (PRE) would be more effective than vector B.
As shown in Figure 2 of the present application, vector B suppressed the expression of the TCR α-chain and β-chain only up to about 80% and 60% respectively, whereas vector D suppressed the expression up to about 30% and about 20% respectively.
Further, Okamoto et al. do not demonstrate the use of 5’ and 3’ LTR sequences and packaging sequence derived from a lentivirus. Instead, Okamoto et al. demonstrates the use of 5’ and 3’ LTR sequences and packaging sequence derived from MMLV which is an oncoretrovirus (see Examples).
Examiners must consider all claim limitations when determining patentability of an invention over the prior art. MPEP §2143/03.
Neither Okamoto nor Mineno teach that the nucleic acid construct does not comprise a promoter sequence between “(c) a sequence of the gene of interest or a multiple cloning site” and “(e) an siRNA-producing sequence”, as recited in the amended claims. In contrast, the claimed nucleic acid construct of the present application (i) comprises 5’ and 3’ LTR sequences and packaging sequence derived from a lentivirus, and (ii) does not comprise a promoter sequence between (c) and (e). The limitation (ii) particularly excludes nucleic acid constructs having unstable suppression of gene expression as shown in Example 5 of the specification. The combination of references fails to teach or suggest each and every limitation of claim 1 and its dependent claims, and the claims are not prima facie obvious over the combined references.
Applicant’s arguments are not persuasive because:
Regarding Applicant’s alleged unexpected results, that placing an siRNA-producing sequence at the position downstream of a WPRE sequence and upstream of a 3’ LTR produces unexpectedly high gene expression, such evidence must be statistically significant. MPEP §716.02b states that the evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration.") In the instant case, Applicant points to figure 2 of the specification to show that vector B suppressed the expression of the TCR α-chain and β-chain only up to about 80% and 60% respectively, whereas vector D suppressed the expression up to about 30% and about 20% respectively; however, figure 2 has no statistics or indication of replicates. Accordingly, it has not been established that the results are different in a statistically significant way. Additionally, Figure 2 also shows that vector C exhibits a similar decrease of TCR levels, yet is a different configuration than the instant claims. Therefore, Applicant’s argument is not persuasive. Furthermore, the claims are not commensurate in scope to vector D of Figure 1. No claim is drawn to vector D, and the claims do not require each specific component of vector D.
Even if the differences were statistically significant, that is not a surprising and unexpected result, because the cited references demonstrate that the configuration of the elements of the nucleic acid construct can influence their expression levels. Okamoto presents several different vectors with the siRNA cassette at different positions (Fig. 8). Among the vector configurations disclosed by Okamoto are the siRNA cassette being in the region of the SD/SA sequences, as mentioned by Applicant, as well as the siRNA cassette being at the end of the vector, next to the 3’ LTR (Fig. 8). Notably, Okamoto also discloses that each of these orientations resulted in expression of the transgene, with levels being similar (Fig. 9). The claimed vector configuration would be obvious to one of ordinary skill in the art upon reading Mineno and Okamoto for the reasons described above in the rejection under 35 U.S.C. §103. Additionally, the instant claims do not exclude a PRE 3’ to the siRNA, which one of ordinary skill in the art would expect to greatly enhance the efficacy of the siRNA and so structures encompassed by claim 1 with better siRNA expression than some other vectors is predictable. One of ordinary skill in the art would have a reasonable expectation of success given that Okamoto demonstrates expression of a gene of interest with each configuration of the vector elements (i.e., siRNA near SD and SA sequences or wherein the siRNA cassette is immediately prior to the 3’LTR). Additionally, there are a finite number of positions for the components of the nucleic acid construct to fill, so any combination thereof would have been obvious.
Mineno discloses that PREs increase stability of mRNA, and the PRE is generally present to the 3’ direction of the desired gene (pp. 2-3). Along those lines, the prior art recognizes that WPRE is most effective when placed downstream of the transgene, proximal to the polyadenylation signal (Higashimoto, et al. Gene Therapy 14, 1298-1304. 2007). The instant specification indicates that a posttranscriptional regulatory element refers to a sequence that contributes the promotion of polyadenylation of mRNA transcribed from a gene in cells, the promotion of nuclear export of mRNA, or the activation of mRNA translation (para. [0018]).
Regarding Applicant’s assertion that Okamoto et al. do not demonstrate the use of 5’ and 3’ LTR sequences and packaging sequence derived from a lentivirus, but instead the use of 5’ and 3’ LTR sequences and packaging sequence derived from MMLV which is an oncoretrovirus in Okamoto’s examples, that argument is not persuasive, because Okamoto’s claims a retroviral containing retroviral 5’ and 3’ UTRs and packaging signal sequence, which the claims indicate can be a lentivirus. Further, even if they did not, it would have been obvious to a person having ordinary skill in the art to utilize a lentiviral vector with these components, as a lentivirus is a type of retrovirus that is commonly used as a viral vector for gene delivery in the art.
Applicant’s argument that neither Okamoto nor Mineno teach that the nucleic acid construct does not comprise a promoter sequence between “(c) a sequence of the gene of interest or a multiple cloning site” and “(e) an siRNA-producing sequence”, as recited in the amended claims, is not persuasive because neither of the cited references disclose that a promoter must be present there, so it would be reasonable to expect that none is present.
New Rejections
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 1-9 and 14-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for an isolated nucleic acid construct for expressing a gene of interest, comprising: in order from the 5’ end to 3’ end, (a) a 5’ LTR sequence derived from a lentivirus, (b) a packaging signal sequence derived from a lentivirus, (c) a sequence of the gene of interest or a multiple cloning site, (d) a PRE, (e) an siRNA-producing sequence which is transcribed into an RNA that forms at least one stem-loop structure and induces RNA interference in a mammalian cell, and (f) a 3’ LTR sequence derived from a lentivirus, wherein the nucleic acid construct does not comprise a promoter sequence between (c) and (e), a retroviral vector comprising a transcript from the nucleic acid construct, and a cell containing the nucleic acid construct, does not reasonably provide enablement for all nucleic acid constructs for expressing a gene of interest, comprising: in order from the 5’ end to 3’ end, (a) a 5’ LTR sequence derived from a lentivirus, (b) a packaging signal sequence derived from a lentivirus, (c) a sequence of the gene of interest or a multiple cloning site, (d) a PRE, (e) an siRNA-producing sequence which is transcribed into an RNA that forms at least one stem-loop structure and induces RNA interference in a mammalian cell, and (f) a 3’ LTR sequence derived from a lentivirus, wherein the nucleic acid construct does not comprise a promoter sequence between (c) and (e), retroviral vectors comprising a transcript from the nucleic acid construct, and cells containing the nucleic acid construct. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
Applicant broadly claims a nucleic acid construct (claims 1-8), retroviral vector comprising a transcript from the nucleic acid construct (claim 9), and a cell containing the nucleic acid construct (claims 14-15). The claims read on a cell within a transgenic animal or a transgene therein given that the term "isolated" is not denoted in describing the host cell, nucleic acid, or vector.
With respect to the unisolated host cells and transgenes as “nucleic acids” or “vectors “of the instant claims discussed above, the state of the art at the time of filing was such that one of skill could not predict the phenotype of transgenics. The art of transgenic animals has for many years stated that the unpredictability lies, in part, with the site or sites of transgene integration into the target genome and that "the position effect" as well as unidentified control elements are recognized to cause aberrant expression of a transgene (Wall et al., Theriogenology, Vol. 45, Pg. 57-68, 1996).
The elements of the particular construct used to make transgenic animals are also held to be critical, and they must be designed case by case without general rules to obtain good expression of a transgene; e.g., specific promoters, presence or absence of introns, etc. (Houdebine et al., Journal of Biotechnology, Vol. 34, Pg. 269- 287, 1994). Furthermore, transgenic animals are regarded to have within their cells, cellular mechanisms that prevent expression of the transgene, such as methylation or deletion from the genome (Kappell et al., Current Opinions in Biotechnology, Vol. 3, Pg. 548-553, 1992). Houdebine (Comparative Immunology, Microbiology, and Infectious Diseases, Vol. 32, Pg. 107-121, 2009) teaches progress has been made in the field of transgenic animals for production of foreign proteins (Abstract); however, constructing an efficient expression vector to produce a therapeutic protein is not a standard operation (Pg. 116, Paragraph, second). Therefore, undue experimentation is required to make and use a transgene and transgenic animal to produce gene of interest and siRNA-producing sequence of the instant claims.
Examples in the literature aptly demonstrate that even closely related species carrying the same transgene construct can exhibit widely varying phenotypes. Mullins (1993, Hypertension, Vol. 22, No. 4, pp. 630-633) states that not all animals express a transgene sufficiently to provide a model for a disease as the integration of a transgene into different species of animal has been reported to give divergent phenotypes. For example, several animal models of human diseases have relied on transgenic rats when the development of mouse models was not feasible. Mullins (1990, Nature, Vol. 344, 541-544) produced outbred Sprague-Dawley x WKY rats with hypertension caused by expression of a mouse Ren-2 renin transgene. Hammer (1990, Cell, Vol. 63, 1099- 1112) describes spontaneous inflammatory disease in inbred Fischer and Lewis rats expressing human class I major histocompatibility allele HLA-B27 and human 02- microglobulin transgenes. Both investigations were preceded by the failure to develop human disease-like symptoms in transgenic mice expressing the same transgenes that successfully caused the desired symptoms in transgenic rats (Mullins, 1989, EMBO J., Vol. 8, pages 4065-4072). Thus, the use of nonmurine species for transgenesis will continue to reflect the suitability of a particular species for the specific questions being addressed, bearing in mind that a given construct may react very differently from one species to another.
The examiner notes here, in addition to these issues, even assuming arguendo PHOSITA could make a host organism with functional transgene that encodes the instantly antibody, there is no predictability that the host will survive its expression. The transgene depends on the host for function and harm to the host, including death, renders the transgene nonfunctional and thus not enabled.
At the time of filing, the phenotype of a transgene and transgenic cell contained within any animal was unpredictable. The claims as written, encompassing a transgene and cell in a transgenic animal, is not adequately described in the specification as to prevent excessive experimentation by the public to generate and use the invention. Applicants can obviate the instant rejection by amending the claims to recite the term "isolated" before the recitation, "nucleic acid construct" and “cell” and by amending the polynucleotide, retroviral vector, and cell claims to specify they are not in a transgenic animal. Applicant may consider using purified in such claims if description is appropriate for such a term and it is not redefined away from standard meaning. Method claims using these products should also carry the appropriate adjectives above.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make and use functional nucleic acid constructs, retroviral vectors, and cells that produce the claimed gene of interest and siRNA, with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed gene of interest and siRNA are functional, commensurate in scope with the claimed invention. The same can be said for the transgenes and transgenic animals encompassed by the instant claims. Thus, the claims are rejected here.
Conclusion
No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEFFREY MARK SIFFORD whose telephone number is (571)272-7289. The examiner can normally be reached 8:30 a.m. - 5:30 p.m. ET with alternating Fridays off.
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/JEFFREY MARK SIFFORD/Examiner, Art Unit 1671 /Michael Allen/Supervisory Patent Examiner, Art Unit 1671
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