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 .
Claim Status and Formal Matters
This action is in response to papers filed 6/30/2026.
Claims 113-117, 119-132 are pending.
Claims 113, 116, 121-122, 127 have been amended.
Claim 132 has been added by amendment.
The 112 rejections have been withdrawn in view of the amendments.
All pervious art rejections have been withdrawn in view of the amendment to require SEQ ID NO 5 and SEQ ID NO 6 in the independent claim.
Priority
The instant application was filed 01/23/2025 and is a Divisional of 18209041 , filed 06/13/2023 which is a continuation of 16955715 , filed 06/18/2020, which is a National Stage entry of PCT/US18/66512 with an international filing date: 12/19/2018 and claims priority from provisional application 62607665 , filed 12/19/2017.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 6/30/2026 is being considered by the examiner.
Specification
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required:
Claim 116 has been amended to recite, “chicken beta actin.” Review and searching of specification did not reveal antecedent basis for this limitation.
Response to Arguments
This is a new ground of objection necessitated by amendment.
Claim Objections
Claim 113-117, 119-132 are objected to because of the following informalities:
Clain 113 has been amended to recite, “Vascular Endothelial Growth Factor.” This is not a proper noun or the first word of the claim and thus does not need to be capitalized.
Claim 113 is objected to as it recites “VEGF” but does not recite the full terminology for the acronym (or abbreviation). Claims are more concise when the first time an acronym (or abbreviation) is presented the full terminology is also presented. Finally an acronym (or abbreviation) may have alternative meanings to an artisan.
Claim 116 is objected to as it recites “CAG,” but does not recite the full terminology for the acronym (or abbreviation). Claims are more concise when the first time an acronym (or abbreviation) is presented the full terminology is also presented. Finally an acronym (or abbreviation) may have alternative meanings to an artisan.
Appropriate correction is required.
Response to Arguments
The response traverses the objections in view of the amendments. The issues with respect to VEGF, CBA, CMV and IL2 have been withdrawn.
The response continues by asserting, “POSA would understand that the term "CAG promoter" refers to a promoter having a CMV enhancer and a CBA promoter. See e.g., Alexopoulou AN, et al., "The CMV early enhancer/chicken beta actin (CAG) promoter can be used to drive transgene expression during the differentiation of murine embryonic stem cells into vascular progenitors." BMC Cell Biol. 2008 Jan 11;9:2, PMID: 18190688.” This argument has been thoroughly reviewed but is not considered persuasive as claims are clearer and more concise when the full terminology of acronyms or abbreviations are set forth.
Claim Rejections - 35 USC § 103
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.
Claim(s) 113-117, 119, 122-126. is/are rejected under 35 U.S.C. 103 as being unpatentable over Xie (Gynecol Oncol (2014) Nov;135(2):325-32) and Lebreton (WO2009/058812)
With regards to claim 113, 119 Xie teaches, “ All AAV vectors were based on the non-human primate-derived AAV serotype rh.10 capsid with the expression cassette comprised of the AAV serotype2 5 ′and 3′ inverted terminal repeats flanking the promoter and transgene. For the AAVrh10.BevMab vector, the expression cassette included the cytomegalovirus enhancer chicken β-actin promoter, the anti-human VEGF heavy-chain and light-chain sequences separated by a furin 2A self-cleavage site and rabbit β-globin gene polyadenylation signal. “(methods , adeno-associated virus vectors)
While Xie teaches, “AAVrh.10BevMab, a rhesus serotype 10 adeno-associated viral vector coding for bevacizumab” (abstract), Xie does not specifically teaches SEQ DI NO 5 and SEQ ID NO 6.
However, Lebreton teaches methods of isolating antibodies for VEGF comprising bevacizumab. Lebreton teaches, “Figures 2A and 2B provide the amino acid sequences of the heavy chain (SEQ ID No. 11) and light chain (SEQ ID No. 12) of bevacizumab antibody.”
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to uses the antibody light chain variable domain and antibody heavy chain variable domain of bevacizumab. The artisan would be motivated as Xie suggests, “, “AAVrh.10BevMab, a rhesus serotype 10 adeno-associated viral vector coding for bevacizumab” (abstract),.” The artisan would have a reasonable expectation of success as the artisan is merely using the explicit sequences taught by Lebreton in the AAV bevacizumab of Xie.
With regards to claim 114-116, Xie teaches, “cytomegalovirus enhancer chicken β-actin promoter.” (page 326, 1st column, bottom)
With regards to claim 117, Xie teaches, “rabbit β-globin gene polyadenylation signal.” (page 326, 1st column, bottom)
With regards to claim 122-123, Xie teaches, “ All AAV vectors were based on the non-human primate-derived AAV serotype rh.10 capsid with the expression cassette comprised of the AAV serotype2 5 ′and 3′ inverted terminal repeats flanking the promoter and transgene. For the AAVrh10.BevMab vector, the expression cassette included the cytomegalovirus enhancer chicken β-actin promoter, the anti-human VEGF heavy-chain and light-chain sequences separated by a furin 2A self-cleavage site and rabbit β-globin gene polyadenylation signal. “(methods , adeno-associated virus vectors)
With regards to claim 124, Xie teaches, “The purified AAV vector was concentrated using an Amicon Ultra-15 100 K centrifuge filter devices (Millipore, Billerica, MA) and stored in phosphate-buffered saline (PBS, pH = 7.4) at −80 °C. Vector genome titers were determined by quantitative TaqMan real-time PCR using a chicken β-actin promoter-specific primer-probe set (Applied Biosystems, Foster City, CA).” (page 326, 2nd column, top)
Claim 125 recites, “wherein the composition is formulated for administration to the inner ear.” This does not explicitly change the structure or composition of the composition. Thus this is obvious over the teachings of Xie and Lebreton.
With regards to claim 126, XI teaches, “To produce the AAVrh.10 vectors, pAAVαVEGF or pAAVαPA (600 μg) and pPAK helper plasmid (1200 μg) were co-transfected into human embryonic kidney 293T cells in 40 150 mm petri-dish using pEI”max”.” (page 326, 2nd column, top)
AS Lebreton teaches, “Figures 2A and 2B provide the amino acid sequences of the heavy chain (SEQ ID No. 11) and light chain (SEQ ID No. 12) of bevacizumab antibody .”
Designing a vector encoding known amino acid sequences , which are equivalents to those taught in the art is routine experimentation. The prior art of Lebreton teaches the amino acid sequence of bevacizumab antibody. The prior art is replete with guidance and information necessary to permit the ordinary artisan to design or determine nucleic acids encoding bevacizumab antibody, as evidence by Xie. As discussed above, the ordinary artisan would be motivated to have designed and tested new vector sequence to improve expression of bevacizumab antibody. The ordinary artisan would have a reasonable expectation of success as Xie demonstrates designing vectors which encode bevacizumab antibody were known.
Thus it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to make an AAV vector encoding SEQ ID NO 5 and SEQ ID NO 6 and having 96% sequence identity with SEQ ID NO 40 and SEQ ID NO 44. The artisan would be motivated as Xie teaches an AAV for producing bevacizumab antibody. The artisan would have a reasonable expectation of success as the artisan is merely using known methods.
Response to Arguments
This is a new ground of rejection necessitated by amendment.
With respect to the previous rejection the response asserts the previously cited prior art does not provide motivation to combine SEQ ID NO 5 and SEQ ID NO 6. This argument has been thoroughly reviewed but is not considered persuasive as Lebreton teach SEQ ID NO 5 and SEQ ID NO 6 as bevacizumab.
Claim(s) 120is/are rejected under 35 U.S.C. 103 as being unpatentable over Xie (Gynecol Oncol (2014) Nov;135(2):325-32) and Lebreton (WO2009/058812 as applied to claims 113-117, 119, 122-126, 132 above, and further in view of Szymczak (Nature Biotechnology (2004, volume 22, pages 589-594.
The teachings Xie and Lebreton are set forth above.
While the teachings of Xie and Lebreton suggest AAV constructs encoding bevacizumab. They do not specifically teach the use of an thosea asigna virus 2A peptide.
However, Szymczak teaches, “Several viruses use 2A peptides, or 2A-like sequences, to mediate protein cleavage2,4. These include members of the Picornaviridae virus family, such as foot-and-mouth disease virus (FMDV) and equine rhinitis A virus (ERAV), and other viruses such as the porcine teschovirus-1 and the insect virus Thosea asigna virus (TaV)3. The 2A peptide consensus motif (2A, Asp-Val/Ile-Glu-X-Asn-Pro-Gly; 2B, Pro) is extremely rare and is always associated with cleavage activity between the 2A glycine and the 2B proline (Fig. 1a).” Szymczak teaches, “Several difficulties have been reported in the use of IRES elements and additional promoters in multicistronic vectors. The larger size of IRES elements and additional promoters, compared with 2A sequences, can be a substantial limitation for vectors with limited cloning capacity, such as rAAV and retroviral vectors14 and may also lead to reduced viral titers15. Additionally, internal promoters can be downregulated in retroviral vectors through promoter interference16. Furthermore, the use of multiple IRES elements can lead to competition for translation factors and/or homologous recombination17 and can vary profoundly in different cell types18. Lastly, IRES-dependent expression can be significantly lower than cap-dependent expression19. All of these problems are reduced or eliminated with the use of 2A peptide–based vectors. Particularly appealing aspects of this technology are the very small size of the 2A peptides and the fact that this cleavage event does not appear to be influenced by external factors, as is seen with internal promoters and IRES. In addition, we have effectively used the 2A peptide as a tag for protein identification using an anti-2A peptide antisera (data not shown). A potential drawback of this system is the possibility that the small, 2A tag left at the end of the N-terminal protein may affect protein function or contribute to the antigenicity of the proteins. However, we have not yet observed these problems in our studies.”
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to use thosea asigna virus 2A peptide in the AAV construct. The artisan would be motivated as the use of thosea asigna virus 2A peptide would decrease the problems associated with IRES sequences. The artisan would have a reasonable expectation of success as the artisan is merely known sequences in known constructs.
Response to Arguments
This is a new ground of rejection necessitated by amendment
Claim(s) 121 is/are rejected under 35 U.S.C. 103 as being unpatentable over Xie (Gynecol Oncol (2014) Nov;135(2):325-32) and Lebreton (WO2009/058812) as applied to claims 113-117, 119, 122-126, 132 above, and further in view of Zhang (J Gene Med 2005; 7: 354–365)
The teachings of Xie and Lebreton are set forth above.
While the teachings of Xie and Lebreton suggest AAV constructs encoding bevacizumab. They do not specifically teach the use of IL2 signal peptide.
However, Zhang teaches, “We chose IL-2 as the signal peptide sequence for amino acid substitution because it is commonly used in both commercial protein production and gene therapy research [22–28]” (pge 355, 2nd column, top)
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to use the IL-2 signal peptide to enhance secretion of bevacizumab. The artisan would be motivated to use IL2 signal peptide as Zhang teaches it is commonly used in both commercial protein production and gene therapy research. The artisan would have a reasonable expectation of success as the artisan is merely using known secretion signal peptides to enhance secretion of bevacizumab.
Response to Arguments
This is a new ground of rejection necessitated by amendment.
Claim(s) 127-131 is/are rejected under 35 U.S.C. 103 as being unpatentable over Xie (Gynecol Oncol (2014) Nov;135(2):325-32) and Lebreton (WO2009/058812) as applied to claims 113-117, 119, 122-126, 132 above, and further in view of Gao (Proceedings National Academy of Sciences USA (2015) (vol 112) pages 14676-14681) and London (Laryngoscope, 124:E340–E346, 20)
The art of Xie and Lebreton teach AAV encoding bevacizumab.
Xie and Lebreton do not teach treating an inner ear disorder.
However, Gao teaches, “In our study, first, we used the sciatic nerve model to characterize the effect and mechanisms of anti-VEGF treatment on neurological function. We revealed that anti-VEGF treatment alleviates tumor edema, which may further result in decreasing muscle atrophy and increasing nerve regeneration and, thus, improves neurological function. Second, we used the intracranial window model to monitor in real time the effect of anti-VEGF treatment on tumor vasculature. We showed that anti-VEGF treatment transiently normalizes the tumor vasculature, leading to improved perfusion and oxygen delivery. Using intravital microscopy imaging technique, we further defined the timing of this transient effect, termed the “normalization window,” in schwannoma models. Because oxygen is a potent radiosensitizer, finally, we showed that radiation therapy applied during the normalization window is most effective, and combined anti-VEGF and radiation therapy is superior to each monotherapy. Anti-VEGF and radiation combination therapy may thus help reduce the dose of each therapy and minimize treatment-associated adverse effect in NF2 patients.” (14676, 2nd column)
London teaches, “Neovascularization has been implicated as a potential contributor to VS disease progression. Tumor size has been correlated with extravasation of blood cells (an indicator of permeability) as well as with quantity of hyalinized vessels.17 VEGF expression as assessed by semiquantitative immunohistochemical staining was found in VSs to correlate with the tumor growth rate.18 Cay_e-Thomasen et al. also reported a correlation between VEGF and VEGFR-1 concentrations and tumor growth rate.19 Koutsimpelas et al. discovered a significant correlation of both VEGF mRNA and protein with schwannomas growth index and microvessel density levels. 20 Although these studies were conducted in sporadic unilateral VSs, Saito et al. reported VEGF immunostaining in 8 of 10 schwannomas from NF2 or probable NF2 patients.21 Collectively, these studies suggest that VEGF and angiogenesis play a significant role in VS disease progression.” London teaches, “As systemic IV treatment with anti-VEGF therapy poses many potential side effects, a recent study investigated endovascular targeted bevacizumab therapy after mannitol blood-brain barrier disruption.25 The study reported a short-term reduction in VS tumor size and improved hearing after a single administration. These results offer a potential therapeutic approach to circumvent side effects of systemic bevacizumab. Lastly, promising results including volumetric and hearing responses from a 21-patient phase II trial have been reported using lapatinib, a HER2/neu and EGFR inhibitor, to treat NF2 patients with progressive VS.26” (E341, 2nd column)
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to treat inner ear with the AAV encoding bevacizumab. The artisan would be motivated to get persistent expression of bevacizumab in the inner ear (cochlear)in subjects. The artisan would be motivated to avoid systemic issues taught by London. The artisan would have a reasonable expectation of success as Shu teaches AAV for treatment of inner ear. (claims 127-131)
Response to Arguments
The response begins traversing the prior rejection asserting Watanbe does not teach the claimed antibody. This argument has been thoroughly reviewed but is not considered persuasive in view of the teachings of Xie and Lebreton.
The response continues traversing the rejection by providing arguments with respect to Gao and lack of persistent bevacizumab. This argument has been thoroughly reviewed but is not considered persuasive as the use of an adenoassociated virus provides for more persistent expression of the gene in the vector, thus addressing the issue with persistence.
The response continues by arguing the teachings of Shu which are not persuasive as they are no longer relied upon.
The response continues by asserting there is no reasonable expectation of success. 2143.02(II) states:
Obviousness does not require absolute predictability, however, at least some degree of predictability is required.
Obviousness cannot be avoided simply by a showing of some degree of unpredictability in the art so long as there was a reasonable probability of success. See In re Corkill, 771 F.2d 1496, 1500 (Fed.Cir.1985) ("Although [the inventor] declared that it cannot be predicted how any candidate will work in a detergent composition, but that it must be tested, this does not overcome [the prior art's] teaching that hydrated zeolites will work."); see also Brown & Williamson Tobacco Corp. v. Philip Morris Inc., 229 F.3d 1120, 1125 (Fed.Cir.2000); Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804, 809 (Fed.Cir.1989); In re Merck & Co., Inc., 800 F.2d 1091, 1097 (Fed.Cir. 1986). Indeed, a rule of law equating unpredictability to patentability, applied in this case, would mean any new treatment or mode of treatment is patenable. This cannot be the proper standard since the expectation of success need only be reasonable, not absolute. Merck, 874 F.2d at 809; In re O'Farrell, 853 F.2d 894, 903 (Fed.Cir. 1988). The evidence would convince a reasonable finder of fact that the skilled artisan would have had a reasonable expectation of success treating the inner ear of a subject with AAV bevacizumab and would work for its intended purpose. See In re Rinehart, 531 F.2d 1048, 1053-54 (C.C.P.A.1976).
Office personnel should not withdraw any rejection solely on the basis that the invention lies in a technological area ordinarily considered to be unpredictable. See MPEP § 2145(X)(E).
Summary
No claims are allowed.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/Steven Pohnert/Primary Examiner, Art Unit 1683
