The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This office action is in response to Applicants’ amendments/remarks received April 22, 2026.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.
Claims 1-9, 13 are canceled. Claims 10-12, 14-18, 19-28 are pending and under consideration.
Priority: This application is a 371 of PCT/JP2021/042463, filed November 18, 2021, which claims benefit of foreign applications JP 2021-145795, filed September 7, 2021, and JP-2020-192844, filed November 19, 2020. Copies of the foreign priority documents have been received in the instant application on May 19, 2023 and are not in the English language.
Objections and Rejections
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 10-12, 14-18, 19-28 are rejected under 35 U.S.C. 103 as being unpatentable over Park et al. (2003 Experimental and Molecular Medicine 35(6): 494-500; IDS 10.04.23, previously cited) in view of Panakanti (Therapeutic Gene Delivery to Human Pancreatic Islets for Treatment of Diabetes and the Effect of TFO on Liver Fibrosis Induced by Bile Duct Ligation (2010) Theses and Dissertations (ETD). Paper 206. (121 pages); previously cited).
Park et al. disclose adenoviral mediated hepatocyte growth factor (HGF) gene attenuates hyperglycemia and beta cell destruction in overt diabetic mice (at least p. 494). Park et al. disclose constructing a recombinant adenoviral vector encoding human HGF (hHGF) (Ad.hHGF) and administering the recombinant vector expressing hHGF to a diabetic mammal at dose 1 x 1011 particles of Ad.hHGF (at least p. 495). Park et al. disclose the recombinant adenoviral vector comprises hHGF cDNA under the control of CMV immediate early enhancer/promoter (at least p. 495). Park et al. disclose Ad.hHGF attenuates hyperglycemia and increases expression of insulin in diabetic mice (at least p. 497-498). Park et al. disclose that the in vivo results suggest that adenoviral mediated hHGF gene therapy has beneficial effect on glucose in advanced diabetic phase and may serve as a therapeutic application for clinically overt diabetic patients (at least p. 499). Therefore, Park et al. disclose administering a viral vector encoding the same therapeutic product (HGF) recited to a mammal for treating the same condition recited and at a dose that is similar to the recited dose. Park et al. do not teach a CA promoter.
Panakanti also discloses utilizing adenoviral vectors encoding proteins, including HGF, for treatment of diabetes (abstract). Panakanti discloses that sustained gene expression is difficult to achieve; however, some promoters have been reported to confer sustained gene expression from plasmid DNA in vivo; these promoters include β-actin, elongation factor 1-α (EF1-α), or ubiquitin (p. 7). Panakanti discloses that the activity of these promoters is usually lower than that of viral promoters, but can be increased by addition of viral or cellular enhancer components (p. 7). Panakanti discloses CMV early enhancer/chicken β actin (CAG) is a promoter of this kind; it consists of CMV enhancer and first intron of chicken (or human skeletal) β-actin (p. 7). Panakanti discloses that it shows activity similar to CMV promoter and shows greater activity in viral vectors (p. 7). Regarding dose of adenoviral vectors, Panakanti discloses that several studies have shown little induction of inflammatory responses on islets transduced with Adv vectors at low MOI (multiplicity of infection) (p. 43). Panakanti discloses that it has been shown that local delivery of low and intermediate doses of replication deficient Adv vectors (1011 particles) are well tolerated (p. 43-44). Panakanti discloses that it is seen that higher doses of Adv can be detrimental and toxic to islets (p. 58, 66) and that there is a need to decrease the viral dose (p. 65-66).
“[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). MPEP 2144.05.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the CAG promoter of Panakanti for the CMV promoter in the Ad.hHGF administered to a diabetic mammal of Park et al. and to administer the Ad.hHGF having the CAG promoter to a mammal for treating diabetes, where the Ad.hHGF is administered at a dose of about 1011 virus particles (vp)/kg body weight (instant claims 10-11) because the prior art discloses the advantages of a CAG promoter in adenoviral vector delivery and the prior art discloses a method for treating the same condition recited in a mammal comprising administering the same product (adenovirus vector expressing HGF) to the mammal. It would have been further obvious to one of ordinary skill to arrive at the recited dose of 1011 virus particles (vp)/kg body weight by routine optimization because it is similar to the low dose recommendation disclosed in the prior art. One of ordinary skill would have a reasonable expectation of success because promoters for adenoviral vectors encoding therapeutic proteins were known and available in the prior art and the prior art also discloses that adenoviral mediated hHGF gene therapy has beneficial effect on glucose and attenuating hyperglycemia in a diabetic mammal.
Regarding instant claim 12, Park et al. disclose the concentrations of glucose were monitored for 21 days after Ad.hHGF infection (at least p. 497-498). As noted above, “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Therefore, it would have been obvious to one of ordinary skill to arrive at the recited dosing regimen of a single dose or multiple doses at an interval of at least 60 days, by routine optimization.
Regarding instant claims 14, 19, 24, Park et al. disclose that the Ad.hHGF gene therapy into diabetic mice pay prevent the further destruction and present as a beneficial remedy for type I diabetic patients (at least p. 494). Therefore, it would be obvious to one of ordinary skill that the diabetes is a type I diabetes.
Regarding instant claims 15, 20, 25, as noted above, Park et al. disclose that the Ad.hHGF gene therapy into diabetic mice pay prevent the further destruction and present as a beneficial remedy for type I diabetic patients (at least p. 494). Therefore, it would be obvious to one of ordinary skill that the Ad.hHGF gene therapy can be administered to a human patient.
Regarding instant claims 16-18, 21-23, 26-28, Park et al. disclose the Ad.hHGF particles were intravenously injected into a tail vein (at least p. 495). Therefore, it would be obvious to one of ordinary skill that the viral vector can be administered intravenously via a peripheral vein.
Reply: Applicants’ amendments/remarks have been considered but they are not persuasive.
Applicants assert that they have unexpectedly discover that, by using a CAG promoter, a hyperglycemia suppressing effect that is the same as or higher than previously reported can be achieved even at a dose as low as 1/10 to 1/100 of the dose in previous reports.
Applicants’ remarks are not persuasive. In this instance, Panakanti has disclosed the advantages of a CAG promoter over the CMV promoter in the adenovirus vector expressing HGF of Park et al. Panakanti discloses that sustained gene expression is difficult to achieve; however, some promoters have been reported to confer sustained gene expression from plasmid DNA in vivo; these promoters include β-actin, elongation factor 1-α (EF1-α), or ubiquitin (p. 7). Panakanti discloses CMV early enhancer/chicken β actin (CAG) is a promoter of this kind; it consists of CMV enhancer and first intron of chicken (or human skeletal) β-actin (p. 7). Panakanti discloses that it shows activity similar to CMV promoter and shows greater activity in viral vectors (p. 7).
Since it is disclosed and recognized that CAG promoters confer sustained gene expression from plasmid DNA in vivo, it would be obvious to one of ordinary skill that an adenovirus vector expressing HGF, which is already recognized to have a hyperglycemia suppressing effect (Park et al.; Panakanti), under a CAG promoter, will result in sustained and long term expression of the HGF. Since it is further disclosed that higher doses of Adv can be detrimental and toxic to islets (Panakanti p. 58, 66) and that there is a need to decrease the viral dose (Panakanti p. 65-66) and that it has been recognized that low and intermediate doses of Adv vectors (1011 particles) are well tolerated (Panakanti p. 43-44), it would be obvious and not surprising that an adenovirus vector expressing HGF under a CAG promoter can achieve the same hyperglycemia suppressing effect in a diabetic mammal at a low dose 1011 particles because there would still be sustained and long term expression of the HGF in vivo.
Applicants assert that it would have been unpredictable to a person of ordinary skill in the art whether comparable therapeutic efficacy could be maintained or whether adverse effects could be avoided. Applicants assert that such a desirable effect resulting from modifying the promoter would have been unpredictable to a person of ordinary skill in the art because the effects of the change to a CA promoter on the gene expression levels, therapeutic efficacy, and safety would likewise have been unpredictable.
Applicants’ remarks are not persuasive. Both Park et al. and Panakanti disclose utilizing adenoviral vectors encoding HGF for treating diabetes in mammals. Panakanti has also disclosed the advantages of a CAG promoter over the CMV promoter in the adenovirus vector expressing HGF of Park et al., where the CAG promoter has been reported to confer sustained gene expression from plasmid DNA in vivo. Therefore, one of ordinary skill would have a reasonable expectation of success that a CAG promoter can be successfully incorporated into an adenovirus vector expressing HGF for sustained and long term expression of the HGF in vivo, where it would be further obvious that adenovirus vector expressing HGF under a CAG promoter can achieve the same hyperglycemia suppressing effect in a diabetic mammal at a low dose of particles because there would be sustained and long term expression of the HGF in vivo.
Applicants assert that in other words, the present invention simultaneously introduces two interrelated technical modifications, namely a change in promoter and a significant reduction in viral dose relative to the disclosure of Park et al.
Applicants’ remarks are not persuasive. As already noted, the advantages of a CAG promoter has already been recognized in the prior art (see the reasons above). Additionally, it has also been recognized in the prior art that higher doses of Adv can be detrimental and toxic to islets (Panakanti p. 58, 66) and that there is a need to decrease the viral dose (Panakanti p. 65-66) and that it has been recognized that low and intermediate doses of Adv vectors (1011 particles) are well tolerated (Panakanti p. 43-44). Therefore, it would be obvious that an adenovirus vector expressing HGF under a CAG promoter can achieve the same hyperglycemia suppressing effect in a diabetic mammal at a dose lower than Park et al., such as a low dose 1011 particles because there would still be sustained and long term expression of the HGF in vivo.
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Marsha Tsay/Primary Examiner, Art Unit 1656
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