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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 7-20-26 has been entered.
Claims 2, 3, 11-20 have been canceled. Claims 1, 4-10 remain pending.
Applicant's arguments filed 7-20-26 have been fully considered but they are not persuasive.
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 Rejections - 35 USC § 102
The rejection of claims 1, 3-10 under 35 U.S.C. 102a1 as being anticipated by Gao (WO 2018071831) was withdrawn because Gao did not teach intrahippocampal injection of AAV as required in claim 1 (previously in claim 2).
Claim Rejections - 35 USC § 103
A) Claims 1, 4-10 remain rejected under 35 U.S.C. 103 as being unpatentable over Gao (WO 2018071831) in view of Tenenbaum (J. Gene Med., 2004, Vol. 6, pg S212-S222).
Gao taught administering an AAV comprising a capsid with the amino acid sequence of SEQ ID NO: 1 (SEQ ID NO: 941) into a subject intracerebrally (pg 4, line 1) or intracerebroventricularly (pg 65, line 26) (pg 65, Example 4). The vector encodes any of a number of proteins (pg 65, lines 21-27) or iRNA (pg 29, line 2). The target cells are cells of the CNS (pg 51, lines 13-26) as required in claim 1.
Gao did not teach intrahippocampal injection of AAV as required in claim 2.
However, it was well known to administer AAV to the hippocampus as described by Tenenbaum (abstract, Materials and Methods). Therefore, it was well within the skill and knowledge of those in the art to administer AAV specifically to the hippocampus. Furthermore, Gao taught “Recombinant AA Vs may be delivered directly to the CNS or brain by injection into, e.g., the ventricular region, as well as to the striatum (e.g., the caudate nucleus or putamen of the striatum), spinal cord and neuromuscular junction, or cerebellar lobule, with a needle, catheter or related device, using neurosurgical techniques known in the art, such as by stereotactic injection (see, e.g., Stein et al., J Viral 73:3424-3429, 1999; Davidson et al., PNAS 97:3428-3432, 2000; Davidson et al., Nat. Genet. 3:219-223, 1993; and Alisky and Davidson, Hum. Gene Ther. 11:2315-2329, 2000)”. Therefore, modifying the teachings of Gao to the hippocampus is an obvious variant and a matter of design choice to ensure cells of the hippocampus receive treatment.
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to administer AAV to the brain as taught by Gao including the hippocampus as described by Tenenbaum. Those of ordinary skill in the art at the time of filing would have been motivated to modify the teachings of Gao specifically to the hippocampus because it is an obvious variant and a matter of design choice to ensure cells of the hippocampus receive treatment.
The target cells are neurons, astrocytes, or glial cells (pg 51, lines 13-26) as required in claim 4.
The subject is a human (pg 51, line 10) as required in claim 5.
The subject MUST inherently make antibodies against AAV2 when AAV2 is used (pg 60, lines 9-18). Variants of AAV are screened for antibody cross-reactivity (pg 64, lines 23-25). This is equivalent to “characterized by production of anti-AAV2 antibodies” as required in claim 6.
The subject MUST inherently lack “a neutralizing immune response against the rAAV” as required in claim 7 because the capsid variant described by Gao is exactly the same as the one in claim 1.
The nucleic acid has ITRs flanking the transgene (pg 17, line 28; pg 29, line 20 & 28; pg 30, lines 1-5) as required in claim 8.
The nucleic acid has a promoter (pg 31, line 4; pg 63, line 4; pg 64, Table 7, “Promoter”) as required in claim 9.
The vector encodes any of a number of proteins (pg 65, lines 21-27) or iRNA (pg 29, line 2) as required in claim 10.
Response to arguments
Applicants argue those of skill had no reason to change the route of delivery (pg 5, 1st para). Applicants’ argument is not persuasive. Gao taught “Recombinant AA Vs may be delivered directly to the CNS or brain by injection into, e.g., the ventricular region, as well as to the striatum (e.g., the caudate nucleus or putamen of the striatum), spinal cord and neuromuscular junction, or cerebellar lobule, with a needle, catheter or related device, using neurosurgical techniques known in the art, such as by stereotactic injection (see, e.g., Stein et al., J Viral 73:3424-3429, 1999; Davidson et al., PNAS 97:3428-3432, 2000; Davidson et al., Nat. Genet. 3:219-223, 1993; and Alisky and Davidson, Hum. Gene Ther. 11:2315-2329, 2000)”. Therefore, modifying the teachings of Gao to the hippocampus is an obvious variant and a matter of design choice to ensure cells of the hippocampus receive treatment.
Applicants argue those of skill knew AAV2 capsid (i.e. SEQ ID NO:1) “did not transduce brain tissue very efficiently” (pg 5, 1st para). Applicants’ argument is not persuasive. It was known to transduce brain tissue. Period. The amount of efficiency is irrelevant. The claim does not require obtaining a certain level of transduction efficiency, so any amount will do.
Applicants argue the rejection fails to teach why those of skill would have chosen SEQ ID NO: 941 described by Gao to perform the method (pg 5, 2nd para). Applicants’ argument is not persuasive and astounding. This is not an obviousness rejection based on choosing SEQ ID NO: 941 as alternative to the teachings of Gao; it is the basis of Gao because Gao said SEQ ID NO: 941 would work. There is no reason to pick and choose because all embodiment of Gao are enabled, including SEQ ID NO: 941.
Applicants argue “design choice” is misplaced in the rejection (pg 6). Applicants’ argument is not persuasive. Modifying the teachings of Gao to the hippocampus is an obvious variant and a matter of design choice to ensure cells of the hippocampus receive treatment. Those of ordinary skill in the art at the time of filing would have been motivated to change the route of delivery to target the hippocampus.
Applicants argue those of skill would not have known whether changing the teachings of Gao to the hippocampus would have predictably worked in delivery to a CNS cell (pg 6-7). Applicants’ argument is legally, logically, and scientifically unsound because delivery to the cerebrum (Gao) or hippocampus (Tenenbaum) IS to the central nervous system, i.e. hippocampal cells ARE CNS cells. BOTH routes of delivery described by Gao and Tenenbaum result in direct delivery to cells of the CNS.
Applicants argue “unexpected results” on pg 7 because AAVv66 capsid mutant comprising SEQ ID NO: 1 had enhanced AAV production yields, virus stability, and CNS transduction after injection into the hippocampus (pg 6-7). Applicants’ argument is not persuasive because it is legally, logically, and scientifically unsound. The “unexpected results” argument does not begin with what was expected, i.e. Gao taught delivering an AAV comprising SEQ ID NO: 1 to the cerebrum. It does not take secondary considerations into account. Applicants’ argument does not compare what was expected, i.e. delivering an AAV comprising SEQ ID NO: 1 to the cerebrum described by Gao, to applicants results with the AAV is delivered to the hippocampus.
B) Claims 1, 4-10 remain rejected under 35 U.S.C. 103 as being unpatentable over Kanaan (Mol. Therapy-Nucleic Acids, 2017, Vol. 8, pg 184-197) in view of Gao (WO 2018071831).
Kanaan administered AAV encoding GDNF (pg 193, col. 2, “Viral genome and vector packaging”) to a subject into the hippocampus (pg 185, col. 2, line 10). The target cells are cells of the CNS (pg 187, Col. 1, last 7 lines).
Kanaan did not teach the AAV comprised a capsid with the amino acid sequence of SEQ ID NO: 1 as required in claim 1.
However, Gao taught administering an AAV comprising a capsid with the amino acid sequence of SEQ ID NO: 1 (SEQ ID NO: 941) into a subject intracerebrally (pg 4, line 1) or intracerebroventricularly (pg 65, line 26, Example 4). The vector encodes any of a number of proteins (pg 65, lines 21-27) or iRNA (pg 29, line 2).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to administering AAV to a subject as described by Kanaan using an AAV with a capsid that has the amino acid sequence of SEQ ID NO: 1. Those of ordinary skill in the art at the time of filing would have been motivated to do so to improve targeting to neurons as described by Gao.
Kanaan taught the target cells are cells of the CNS (pg 187, col. 1, last 7 lines) as required in claim 3.
The target cells are neurons (pg 187, Fig. 2 caption) as required in claim 4.
The subject is a human (pg 51, line 10 of Gao) as required in claim 5.
The subject MUST inherently make antibodies against AAV2 when AAV2 is used (pg 187, Efficacy of transduction). This is equivalent to “characterized by production of anti-AAV2 antibodies” as required in claim 6.
The subject MUST inherently lack “a neutralizing immune response against the rAAV” as required in claim 7 because the method and capsid variant described by the combined teachings of Kanaan and Gao is exactly the same as the one in claim 1.
The nucleic acid has ITRs flanking the transgene (pg 17, line 28; pg 29, line 20 & 28; pg 30, lines 1-5, of Gao) as required in claim 8.
The nucleic acid has a promoter (pg 193, col. 2, 4th paragraph) as required in claim 9.
Kanaan taught the vector encoded GDNF and Gao taught the vector encodes any of a number of proteins (pg 65, lines 21-27) or iRNA (pg 29, line 2) as required in claim 10.
Response to arguments
Applicants argue those of skill would not have any reason to modify the teachings of Kanaan. Applicants’ argument is not persuasive for reasons of record.
Applicants argue there is no reason to select the capsid of SEQ ID NO: 1. Applicants’ argument is not persuasive because Gao taught administering an AAV comprising a capsid with the amino acid sequence of SEQ ID NO: 1 (SEQ ID NO: 941) into a subject for targeting neurons intracerebrally (pg 4, line 1) or intracerebroventricularly (pg 65, line 26, Example 4).
Applicants argue “unexpected results” on pg 9-10 because AAVv66 capsid mutant comprising SEQ ID NO: 1 had enhanced AAV production yields, virus stability, and CNS transduction after injection into the hippocampus as compared to AAV2. Applicants’ argument is not persuasive because it is legally, logically, and scientifically unsound. The “unexpected results” argument does not begin with what was expected, i.e. Kanaan taught delivering an AAV2 into the hippocampus. It does not take secondary considerations into account. There is nothing in the specification comparing what was expected, i.e. delivering an AAV2 into the hippocampus described by Kanaan, to applicants results with the AAV comprising SEQ ID NO: 1 is delivered to the hippocampus.
Conclusion
No claim is allowed.
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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638
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