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 .
1. Claims 2, 3, 5, 7, 12, 17, 20, 21, 23-29, and 34-37 have been cancelled. Claims 1, 4, 6, 8, 11, 14, 18, and 22 have been amended.
Claims 1, 4, 6, 8-11, 13-16, 18, 19, 22, and 30-33 are pending and under examination.
2. All rejections/objections pertaining to claims 2 and 24 are moot because the claims were cancelled with the reply filed on 11/12/025.
The objections to claims 4, 6, 8, 11, and 14-16 are withdrawn in response to the amendments filed on 11/12/025.
The rejection of claim 16 under 35 U.S.C. 112(d)is withdrawn in response to the amendment to the parent claim 15 deleting the recitation of a promoter directing expression in hepatic cells.
Claim Rejections - 35 USC § 103
3. 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.
4. 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 Ananth et al. (Colloids and Surfaces B: Biointerfaces, 2011, 85: 138-144).
Wang et al. also teach that HSA enhances transduction efficiency of different AAV serotypes, including AAV1-6, 8, and 9. Wang et al. teach treating hemophilia B by co-administering human serum albumin (HSA) and an rAVV8 encoding FIX from the TTR promoter to a model of hemophilia B, where the rAAV8 transduces hepatocytes and where HSA enhances transduction efficiency; the rAAV8 is incubated with the HSA for 60 min before administration; 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. 56, column 2, third full paragraph; paragraph bridging p. 56 and 57; p. 57, column 1, first full paragraph). While Wang et al. do not specifically teach 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).
Wang 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. 141, 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 AAV1-6, 8, and 9 (claim 1), with the reasonable expectation that doing so would result in enhanced transduction efficiency from these AAVs.
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.
5. 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 Ananth et al., in further view of Prabha et al. (Pharm. Res., 2004, 21: 354-364).
The teachings of Wang 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. 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.
6. 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 Ananth et al., in further view of Aslanidi et al. (WO 16/134338).
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. 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. 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.
7. 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 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. 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
8. The arguments addressing the references individually are not found persuasive because none of the references has to teach every claim limitation. 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 references suggest that replacing HAS with PVA would result in enhanced transduction efficiency.
The applicant argues lack of reasonable expectation of success because silver nanoparticles are structurally and functionally different from AAVs, the same being true for HAS and PVA.
This is not found persuasive because it is just an argument not supported by any evidence. Structural difference is not evidence for lack of reasonable expectation of success. The cited prior art teaches that, albeit structural differences, albumin is capable of mediating liver delivery for both AAVs and silver nanoparticles. The cited prior art also teaches that, similar to albumin, PVA mediates the delivery of silver nanoparticles to the liver. One of skill in the art would have reasonably concluded that albumin and PVA are functional equivalents with respect to liver delivery and would have reasonably expected to be successful in replacing albumin with PVA. There is no evidence to the contrary of record.
The applicant argues that none of Prabha, Aslanidi, Chang, MacLaren, and Boye remedies the deficiencies of Wang and Ananth.
This is not found persuasive because there is no deficiency to be cured in the combined teachings of Wang and Ananth.
Conclusion
9. 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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/ILEANA POPA/Primary Examiner, Art Unit 1633