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
1. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/28/2026 has been entered.
Claims 2, 3, 5, 7, 12, 17, 20, 21, 23-29, and 34-37 have been cancelled.
Claims 1, 4, 6, 8-11, 13-16, 18, 19, 22, and 30-33 are pending and under examination.
Claim Rejections - 35 USC § 103
2. 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.
3. Claims 1, 4, 6, 8-11, 14-16, 18, 19, 22, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (Gene Therapy, 2017, 24: 49-59), in view of both Grimm et al. (Blood, 2003, 102: 2412-2419) and Ananth et al. (Colloids and Surfaces B: Biointerfaces, 2011, 85: 138-144).
Wang et al. teach that HSA enhances transduction efficiency of different rAAV serotypes (including rAAV1-6, 8, and 9) in hepatocytes in vitro. Wang et al. exemplify treating hemophilia B by co-administering an rAVV8 expressing FIX from the TTR promoter and human serum albumin (HSA) to a mouse model of hemophilia B; the rAAV8 transduces hepatocytes and HSA enhances transduction efficiency; the rAAV8 is incubated with the HSA for 60 min before administration to let HSA interact with the AAV capsid, which increases transduction efficiency; administration is intravenous and entails injecting 2 x 109 rAAV particles/HSA (claims 1, 4, 6, 11, 14-16, 18, 19, and 22) (see Abstract; p. 49; paragraph bridging p. 50 and 51; p. 51, Fig. 1; p. 55, paragraph bridging columns 1 and 2; p. 56, column 2, first and third full paragraphs; paragraph bridging p. 56 and 57; p. 57, column 1, first full paragraph). While Wang et al. do not specify the volume containing the 2 x 109 rAAV particles, one of skill in the art would have found obvious to optimize delivery by suspending the viral particles in different volumes (including less or more than 1 ml) by just using routine experimentation (claim 9). Since Wang et al. teach therapeutic effect, FIX production must necessarily preserve one or more of the hepatic cells in the mouse (claim 31).
While Wang et al. do not exemplify treating hemophilia B by co-administering rAAV3 or rAAV6/HSA (claim 1), based on the in vitro results, one of skill in the art
would have reasonably concluded that rAVV8 could be replaced with rAAV3 or rAAV6 and would have found obvious use either one with the reasonable expectation that doing so would result in hemophilia B in the mouse model. Especially in view of Grimm et al. teaching that rAAV3 and rAAV6 can successfully deliver FIX to human hepatocytes in vitro and to the mouse liver in vivo, evidencing that the in vitro results could be extrapolated to therapy in vivo (see p. 2413, Fig. 1C; paragraph bridging p. 2414 and 2415; p. 2415, Fig. 2; p. 2419, paragraph bridging columns 1 and 2 and column 2, last paragraph).
Wang et al. and Grimm et al. do not teach PVA (claim 1). However, using PVA is suggested by the prior art. For example, Ananth et al. teach that PVA is better than serum albumin in mediating delivery to the liver (see Abstract; p. 139, column 2, second paragraph; p. 141, column 1 and Fig. 4). Based on these teachings, one of skill in the art would have found obvious to modify Wang et al. by replacing HSA with PVA for any of rAAV3 and rAAV6 (claim 1), with the reasonable expectation that doing so would enhance their transduction efficiency.
With respect to claim 10, there is no evidence of unexpected results associated with using less than 1 x 109 rAAV particles. Furthermore, since the prior art teaches that PVA is more efficient than HSA, one of skill in the art would have reasonably concluded that the method could be practiced with less than 2 x 109 rAAV particles. One of skill in the art would have found obvious to use routine experimentation and vary the rAAV titer with the reasonable expectation that doing so would identify the optimal transduction conditions. Similar considerations apply to claim 8, as there is no evidence of record showing unexpected results associated with the recited concentrations. Optimizing the PVA concentration would have only required routine experimentation and would have been obvious to one of skill in the art with the reasonable expectation that doing so would identify the optimal transduction conditions. Routine optimization is not considered inventive and no evidence has been presented that the selection the claimed titer was other than routine or that the results should be considered unexpected in any way as compared to the closest prior art (see MPEP 2144.05 II).
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
4. Claims 1, 4, 6, 8-11, 13-16, 18, 19, 22, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. taken with both Grimm et al. and Ananth et al., in further view of Prabha et al. (Pharm. Res., 2004, 21: 354-364).
The teachings of Wang et al., Grimm et al., and Ananth et al. are applied as above for claims 1, 4, 6, 8-11, 14-16, 18, 19, 22, and 31. Wang et al., Grimm et al., and Ananth et al. do not specifically teach that the PVA is 87% hydrolyzed (claim 13). Prabha et al. teach that 89% hydrolyzed PVA is suitable for introducing nucleic acids into cells (see p. 360, column 2; p. 363, column 2, last paragraph). Using an 88% hydrolyzed PVA would have been obvious to one of skill in the art with the reasonable expectation that doing so would result in enhanced transduction. While 88% is not exactly 87%, as per MPEP § 716.02, [a]ny differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, there is no evidence of record indicating that 87% hydrolyzation results in unexpected properties over 87% hydrolyzation.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
5. Claims 1, 4, 8-11, 14-16, 18, 19, 22, 30, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. taken with both Grimm et al. and Ananth et al., in further view of Aslanidi et al. (WO 16/134338).
The teachings of Wang et al. ,Grimm et al., and Ananth et al. are applied as above for claims 1, 4, 8-11, 14-16, 18, 19, 22, and 31. Wang et al., Grimm et al., and Ananth et al. do not teach treating β-thalassemia or sickle cell disease (claim 30). However, one of skill in the art would have reasonably concluded that the teachings of Wang et al. and Ananth et al. could be extrapolated to methods for treating diseases other than hemophilia B. Furthermore, Aslanidi et al. teach treating β-thalassemia or sickle cell disease by administering to a subject an rAAV2 or rAAV6 encoding a therapeutic gene (such as β-globin, anti-sickling β-globin, or [Symbol font/0x67]-globin) under the control of the parvovirus B19 promoter (see p. 2 through p. 3, line 4; paragraph bridging p. 3 and 4; p. 4, line 19 through p. 5, line 3; p. 9, lines 3-18). One of skill in the art would have found obvious to modify Wang et al., Grimm et al., and Ananth et al. by using the rAAVs taught by Aslanidi et al., when treating β-thalassemia or sickle cell disease was needed, with the reasonable expectation that doing so would enhance transduction efficiency and therapeutic effect.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
6. Claims 1, 4, 8-11, 14-16, 18, 19, 22, and 30-33 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. taken with both Grimm et al. and Ananth et al., in further view of all Chang et al. (WO 02/088173), MacLaren et al. (WO 19/079488), and Boye et al. (WO 11/133933).
The teachings of Wang et al. and Ananth et al. are applied as above for claims 1, 4, 8-11, 14-16, 18, 19, 22, and 31. Wang et al., Grimm et al., and Ananth et al. do not teach the buffer recited in claims 32 and 33. Chang et al. teach that PBS, Ringer’s solution, and balanced salt solution (BSS) are suitable for formulating AAVs (see p. 18, lines 21-25). One of skill in the art would have found obvious to suspend the rAAV in a solution comprising PVA in PBS, BSS, and Ringer’s solution with the reasonable expectation that doing so would result in a composition suitable for storage and capable of mediating enhanced transduction (claim 32). With respect to claim 33, MacLaren et al. teach that TMN 200 maintains AAV biocompatibility and stability (see [0184]; [0290]-[0291]). Further adding TMN 200 would have been obvious to one of skill in the art to achieve the predictable result of obtaining a formulation for AAV storage and transduction. MPEP 2144.06 [R-6] I states:
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)
While the formulation comprises Ringer’s solution and not lactated Ringer’s solution (claim 33), it is noted that there is no evidence of record indicating that lactated Ringer’s solution provides unexpected results over the Ringer’s solution. As per MPEP § 716.02, [a]ny differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, there is no evidence of unexpected results.
Furthermore, Boye et al. teach that lactated Ringer’s solution is suitable to be used in AAV formulations (see [0090]). Replacing Ringer’s solution with lactated Ringer’s solution would have been obvious to one of skill in the art to achieve the predictable result of obtaining a composition suitable for storage and capable of mediating enhanced transduction.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
Response to Arguments
7. The applicant argues that neither Wang nor Ananth mentions AAV3 or AAV6.
This is not found persuasive. Wang provides data showing that HSA enhances transduction efficiency for AAV3 and AAV6 in vitro (see Fig. 1a). While Wang on;y exemplifies AAV8 for in vivo delivery, replacing the rAAV8 with rAAV3 or rAAV6 would have been obvious (see the rejection).
The argument that Wang does not mention using PVA is not found persuasive because Wang does not have to teach every claim limitation.
The arguments addressing Ananth are not found persuasive. Ananth does not have to mention AAV3 and AAV6 because the reference was cited for providing the motivation to modify Wang by replacing HSA with PVA, not for teaching AAV3 or AAV6.
With respect to the argument that Ananth does not teach co-administration with PVA, it is noted that Ananth teaches administering silver nanoparticles coated with BSA or PVA to a mouse, i.e., co-administering the silver nanoparticles with BSA or PVA. Ananth teaches that co-administration with PVA results in enhanced delivery to the liver compared to co-administration with BSA. One of skill in the art would have reasonably concluded that these teachings could be extrapolated to other albumin-coated particles such as the HSA-coated AAV particles taught by Wang (since Wang teaches that HSA interacts with the AAV capsid, one of skill in the art would have known that the administered AAV is coated with HSA).
The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In this case, the combined teachings of the cited prior art provide the necessary teachings and suggestions to arrive at the claimed invention with a reasonable expectation of success. There is no evidence to the contrary of record.
For these reasons above, the argument that Wang does not teach coating the AAV with HSA is not found persuasive.
In response to applicant's argument that Ananth is nonanalogous art, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, Ananth is pertinent art because the reference teaches how to improve delivery to the liver.
The argument of lack of reasonable expectation of success is not found persuasive because it is just an argument not supported by any evidence.
The argument of unexpected results is not found persuasive because the results are not unexpected over the cited prior art.
The results in the specification demonstrate that preincubation with PVA increases transgene expression and nuclear AAV import as compared to AAV not preincubated with PVA. However, Wang already teaches that coating the AAV with HSA significantly enhances liver transduction and protein expression compared to the uncoated AAV (see p. 54, Fig. 6b and c); since protein expression is significantly enhanced, one of skill in the art would have reasonably concluded that coating with HSA leads to enhanced nuclear import. Since Ananth teaches that PVA provides about 4-fold increase in liver delivery over serum albumin (see Fig. 4), one of skill in the art would have reasonably expected to further enhance transduction and protein expression (and hence, nuclear import) when replacing HSA with PVA. The data in the specification does not show that the invention provides for more than was expected from the teachings in the prior art.
The argument that Prabha, Aslanidi, Chang, MacLaren, Boye do not remedy the deficiencies of Wang and Ananth is not found persuasive because there is no deficiency to be remedied in the combined teachings of Wang and Ananth.
8. No claim is allowed. No claim is free of prior art.
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/ILEANA POPA/Primary Examiner, Art Unit 1633
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