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 .
The response filed 12/10/2025 has been received and entered. Claims 1 and 3-16 remain pending, all of which have been considered on the merits.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claim 7 under 35 U.S.C. 112(b).
Claim 7 has been amended to remove indefinite language. The rejection is thus withdrawn.
RE: Rejection of claims 1, 3, and 8-15 under 35 U.S.C. 103 over Picconi et al (Molecular Therapy, 2014) in view of Onions et al (Diabetes, 2019).
Applicants traverse the rejection of record on the grounds that Picconi et al teaches kidney specific expression is driven by the rAAV 2/9 vector itself rather than the NPHS1 promoter. Applicants point to statements in Picconi et al teaching rAAV2/9 has tissue tropism for the kidney and statements teaching the minimal Nephrin promoter is used to restrict expression to the glomerulus, specifically glomerular basement membrane and podocytes. Additionally, applicants believe Fig. 6c of Picconi fails to demonstrate colocalization of GFP (red) and WT1 (green) and instead shows bleed through from in the GFP (red) into the green channel.
In response, the argument has been fully considered but is not persuasive. Picconi teaches the minimal Nephrin promoter may drive expression in the glomerular basement membrane and podocytes. Thus, the Nephrin promoter drives expression in podocytes. Applicants assertion that the colocalization in Fig. 6c is due to bleed through is not convincing. If the merged signal in Fig. 6c was caused by channel bleed through, one would expect to see overlapping expression that is perfectly matched. However, the brightest merged (yellow) expression correlates with regions of WT1 (green) expression which is in a similar pattern/shape of the WT1 expression in Fig. 6b. Thus, while the method of claims 8-15 has been amended to require expression in podocytes, it does not exclude expression in other cells of the glomeruli/kidney.
However, Applicants have amended claim 1 to recite the limitation “wherein the AAV vector is AAV serotype LK03 or 3B”. Picconi et al and Onions et al do not teach AAVs of serotype LK03 or 3B. Thus, amendments to the claims overcome the rejection of record.
The rejection over claims 1, 3, and 8-15 is withdrawn.
Claim 2 has been cancelled rendering the rejection moot.
RE: Rejection of claims 1, 3-5 and 8-15 under 35 U.S.C. 103 over Picconi et al (Molecular Therapy, 2014) in view of Onions et al (Diabetes, 2019) and Otto Wilhelm et al.
Applicants amended claim 1 to recite the limitation “wherein the AAV vector is AAV serotype LK03 or 3B”. Picconi et al, Onions et al, and Otto Wilhelm et al do not teach AAVs of serotype LK03 or 3B. Thus, amendments to the claims overcome the rejection of record.
The rejection over claims 1, 3-5, and 8-15 is withdrawn.
Claim 2 has been cancelled rendering the rejection moot.
RE: Rejection of claims 1, 3, and 6-15 under 35 U.S.C. 103 over Picconi et al (Molecular Therapy, 2014) in view of Onions et al (Diabetes, 2019) and Makrides et al.
The heading of the rejection, in the non-final rejection (dated 06/25/25) incorrectly stated the rejection was made over Picconi et al in view of Onions et al and Otto Wilhelm et al. While the rejection itself made reference to Picconi et al, Onions et al, and Makrides et al.
Applicants amended claim 1 to recite the limitation “wherein the AAV vector is AAV serotype LK03 or 3B”. Picconi et al, Onions et al, and Makrides et al do not teach AAVs of serotype LK03 or 3B. Thus, amendments to the claims overcome the rejection of record.
The rejection over claims 1, 3, and 6-15 is withdrawn.
Claim 2 has been cancelled rendering the rejection moot.
New Rejections
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, and 8-15 are rejected under 35 U.S.C. 103 as being unpatentable over Picconi et al (Molecular Therapy, 2014) in view of Onions et al (Diabetes, 2019) and Wang et al (Molecular Therapy, 2015), cited in IDS filed 12/10/2025.
Picconi et al teaches a rAAV 2/9 containing a Nephrin (NPHS1) promoter which drives expression of GFP in glomeruli, specifically in the glomerular basement membrane and in podocytes (See Abstract and Discussion). Picconi et al administers the rAAV through tail vein injection into pregnant dams resulting in expression in kidneys of the mother as well as the resulting pups (See Sec. Pregnant mice with kidney-specific promoter and Fig. 6).
Regarding claim 1: Picconi et al teaches a rAAV 2/9 containing a NPHS1 promoter.
Picconi et al does not teach a vector comprising vascular endothelial growth factor C (VEGFC) transgene.
Onions et al teaches a mouse model (podVEGFC) which expresses VEGFC in podocytes in response to doxycycline administration (See Sec. Podocin Reverse Tetracycline-Controlled Transcriptional Activator, Tet-O-VEGFC (podVEGFC) Mice). The podVEGFC mice are used to test the effects of VEGFC overexpression on diabetic nephropathy (DN) in diabetic mouse models. Onions finds that inducing VEGFC expression prior to induction of type I diabetes by STZ injection prevents renal hypertrophy and reduces the ratio of urinary albumin to creatinine (uACR) compared to STZ control mice (See Sec. Early Glomerular VEGFC Expression Reduces the Development of DN). Additionally, Onions teaches inducing VEGFC expression during early stage STZ induced DN, reduces renal hypertrophy and uACR (See Sec. Glomerular VEGFC Intervention Reduces the Development of DN).
Given that Picconi et al teaches a rAAV2/9 vector comprising a NPHS1 promoter which is specifically expressed in the glomerular basement membrane and in podocytes and Onions et al teaches expression of VEGFC in podocytes can prevent DN and rescue early stage DN, it would have been prima facie obvious to modify the vector of Picconi et al to comprise a VEGFC transgene in order to express VEGFC in podocytes. One would have been motivated to make this modification because Onions et al teaches expressing VEGFC in podocytes prevents DN and can treat early-stage DN. There is a reasonable expectation of success because Picconi teaches the vector can be used to deliver a gene therapy vector resulting in stable expression (See Picconi, Discussion at Pg. 14014).
Furthermore, Picconi does not teach an AAV of serotype LK03 or 3B.
Wang et al teaches AAV LK03 and 3B can be detected in the kidney at approximately 1.E+04 (GC/ug) following IV administration (See Fig. 4).
Given that Picconi et al teaches an AAV for expression in the kidney and Wang et al teaches AAV LK03 and 3B can be detected in kidneys, it would have been prima facie obvious to substitute the rAAV2/9 of Picconi et al with the LK03 or 3B AAV of Wang et al. One would have expected the LK03 or 3B AAVs of Wang et al to work equivocally with the rAAV2/9 of Picconi et al because Wang et al teaches AAV LK03 and 3B can be detected in kidneys. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable is considered to be obvious. See KSR International Co. V Teleflex Inc 82 USPQ2d 1385 (US2007) at page 1395.
Regarding claim 3: Following the discussion of claim 1 above, Picconi et al teaches a an AAV containing a NPHS1 promoter.
Picconi et al does not teach a vector comprising vascular endothelial growth factor C (VEGFC) transgene wherein the transgene comprises a polynucleotide encoding a VEGFC prepropeptide, an intermediate form of VEGFC, or a mature form of VEGFC.
Onions et al teaches expressing VEGFC in podocytes can prevent DN and can be used to treat early-stage DN.
Thus, it would have been prima facie obvious to modify the vector of Picconi et al to comprise a VEGFC transgene in order to express VEGFC in podocytes (See discussion of claim 1 above).
Furthermore, it would have been prima facie obvious to express the VEGFC as a prepropeptide, intermediate form of VEGFC, or a mature form of VEGFC because any of these forms will result in expression of VEGFC. There is a motivation to express the VEGFC as a prepropeptide, intermediate form of VEGFC, or a mature form of VEGFC because any of these forms would result in expression of VEGFC. There is a reasonable expectation of success because using rAAVs to express prepropeptides, immature proteins, and mature proteins are all known techniques in the art.
Regarding claims 8-10: Picconi et al teaches a rAAV 2/9 containing a NPHS1 promoter which drives expression in glomerular basement membrane and podocytes.
Picconi et al does not teach a vector comprising vascular endothelial growth factor C (VEGFC) transgene.
Onions et al teaches a mouse model (podVEGFC) which expresses VEGFC in podocytes in response to doxycycline administration (See Sec. Podocin Reverse Tetracycline-Controlled Transcriptional Activator, Tet-O-VEGFC (podVEGFC) Mice). The podVEGFC mice are used to test the effects of VEGFC overexpression on diabetic nephropathy (DN) (reads on a diabetic kidney disease) in diabetic mouse models. Onions finds that inducing VEGFC expression prior to induction of type I diabetes by STZ injection prevents renal hypertrophy and reduces the ratio of urinary albumin to creatinine (uACR) compared to STZ control mice (See Sec. Early Glomerular VEGFC Expression Reduces the Development of DN). Additionally, Onions teaches inducing VEGFC expression during early stage STZ induced DN, reduces renal hypertrophy and uACR (See Sec. Glomerular VEGFC Intervention Reduces the Development of DN).
Given that Picconi et al teaches a rAAV2/9 vector comprising a NPHS1 promoter which is specifically expressed in the glomerular basement membrane and in podocytes and Onions et al teaches expression of VEGFC in podocytes can prevent DN and rescue early stage DN, it would have been prima facie obvious to modify the vector of Picconi et al to comprise a VEGFC transgene in order to use an effective amount of the rAAV to prevent or treat early DN (reads on treating or preventing diabetic kidney disease). One would have been motivated to make this modification because Onions et al teaches expressing VEGFC in podocytes prevents DN and can treat early-stage DN. There is a reasonable expectation of success because Picconi teaches the vector can be used to deliver a gene therapy vector resulting in stable expression.
Furthermore, Picconi does not teach an AAV of serotype LK03 or 3B.
Wang et al teaches AAV LK03 and 3B can be detected in the kidney at approximately 1.E+04 (GC/ug) following IV administration (See Fig. 4).
Given that Picconi et al teaches an AAV for expression in the kidney and Wang et al teaches AAV LK03 and 3B can be detected in kidneys, it would have been prima facie obvious to substitute the rAAV2/9 of Picconi et al with the LK03 or 3B AAV of Wang et al. One would have expected the LK03 or 3B AAVs of Wang et al to work equivocally with the rAAV2/9 of Picconi et al because Wang et al teaches AAV LK03 and 3B can be detected in kidneys. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable is considered to be obvious. See KSR International Co. V Teleflex Inc 82 USPQ2d 1385 (US2007) at page 1395.
Regarding claim 11: Following the discussion of claim 8 above, Picconi et al teaches an AAV containing a NPHS1 promoter.
Picconi et al does not teach using the vector to treat kidney disease in a human patient.
Onions et al teaches VEGFC can ameliorate albuminuria by reducing the permeability of glomerular endothelial cells (GEnC) to protein and improve DN (reads on treating a kidney disease) in experiments using human GEnCs (See Sec. Glomerular VEGFC Expression Affects VEGF Signaling and Fig. 3).
Given that Picconi et al teaches a vector which can be used to drive expression in glomeruli and Onions teaches expression of VEGFC in ameliorate albuminuria (reads on treating kidney disease) in human cells. It would have been prima facie obvious to modify the vector of Picconi et al to express VEGFC in order to treat human patients with DN (reads on treating a subject that is a human patient). One would have been motivated to modify the vector in order to use the vector to treat DN in a human patient. There is a reasonable expectation of success because Onions teaches VEGFC expression improves DN in human cells.
Regarding claims 13 and 14: Following the discussion of claim 8 above, the method of Picconi comprises injecting the rAAV into the tail vein (reads on systemic administration and an intravenous injection) of a pregnant mouse. This injection results in expression of the vector in the glomeruli of the mother as well as the glomeruli of the pups.
Regarding claim 15: Following the discussion of claim 8 above, Picconi et al teaches an rAAV that is expressed in glomeruli.
Picconi et al does not teach administering the rAAV via the renal artery.
Given that blood flows from the renal artery to glomeruli to be filtered, it would have been prima facie obvious to administer the vector by injecting it into the renal artery because blood flows from the renal artery to glomeruli. One would have been motivated to inject the vector into the renal artery because it is a more direct route to the glomeruli than a tail vein injection which would allow more of the vector to reach the glomeruli. There is a reasonable expectation of success because blood flows from the renal artery to glomeruli.
Claims 1, 3-5 and 8-15 are rejected under 35 U.S.C. 103 as being unpatentable over Picconi et al (Molecular Therapy, 2014) in view of Onions et al (Diabetes, 2019), Wang et al (Molecular Therapy, 2015), and Otto Wilhelm et al.
The teachings of Picconi et al, Onions et al, and Wang et al are set forth above.
Picconi et al in view of Onions et al render claims 1, 3, and 8-15 obvious.
Regarding claim 4: Following the discussion of claim 1 above, Picconi et al teaches an rAAV vector comprising a NPHS1 promoter.
Picconi et al does not teach the AAV vector additionally comprises a Woodchuck hepatitis post-transcriptional regulatory element (WPRE).
Otto Wilhelm et al teaches including a WPRE sequence in a vector can increase levels of transcripts expressed by vectors (See pg. 188, last paragraph).
Given that Picconi et al teaches a vector that can be used for gene therapy in the kidneys and Otto Wilhelm et al teaches including a WPRE sequence in a vector can increase levels of transcripts expressed by vectors, it would have been prima facie obvious to include a WPRE sequence in the vector of Picconi in order to express higher levels of VEGFC. One would have been motivated to modify the vector in order to increase the amount of transcript expressed by the vector. There is a reasonable expectation of success because including WPRE sequences in vectors is a known technique in the art.
Regarding claim 5: Following the discussion of claim 1 above, Picconi et al teaches an rAAV vector comprising a NPHS1 promoter.
Picconi et al does not teach the AAV vector additionally comprises a HA tag.
Otto Wilhelm et al teaches including a HA tag in a vector improves binding of the vector with host cells (See pg. 371, second paragraph).
Given that Picconi et al teaches a vector that can be used for gene therapy in the kidneys and Otto Wilhelm et al teaches including a HA tag in a vector can improve binding of vectors to host cells, it would have been prima facie obvious to include a HA tag in the vector of Picconi in order to improve binding of the vector to host cells. One would have been motivated to modify the vector in order improve binding of the vector to host cells. There is a reasonable expectation of success because including a HA tag in vectors is a known technique in the art.
Claims 1, 3, and 6-16 are rejected under 35 U.S.C. 103 as being unpatentable over Picconi et al (Molecular Therapy, 2014) in view of Onions et al (Diabetes, 2019), Wang et al (Molecular Therapy, 2015), and Makrides et al (Gene Transfer and expression in Mammalian Cells, 2003).
The teachings of Picconi et al and Onions et al are set forth above.
Picconi et al in view of Onions et al render claims 1, 3, and 8-15 obvious.
Regarding claim 6: Following the discussion of claim 1 above, Picconi et al teaches an rAAV vector comprising a NPHS1 promoter.
Picconi et al does not teach the AAV vector additionally comprises a Kozak sequence between the promoter and the VEGFC transgene.
Makrides teaches including the Kozak sequence GCC(A/G)CCaugG where the aug is the start codon (reads on between the promoter and the transgene) facilitates optimal translation initiation (See pg. 20, Sec. 5’Untranslated region).
Given that Picconi et al teaches a vector that can be used for gene therapy in the kidneys and Makrides teaches including a Kozak sequence between the promoter and the transgene facilitates optimal translation initiation, it would have been prima facie obvious to include a Kozak sequence between the promoter and transgene in the vector of Picconi in order to facilitate optimal translation. One would have been motivated to modify the vector in order facilitate optimal translation initiation of the transgene. There is a reasonable expectation of success because including a Kozak sequence between the promoter and transgene in a vector is a known technique in the art.
Regarding claims 7 and 16: Following the discussion of claim 1 above, Picconi et al teaches an rAAV vector comprising a NPHS1 promoter.
Picconi et al does not teach the AAV vector additionally comprises a bovine growth hormone (bGH) polyadenylation signal.
Makrides teaches a polyadenylation (polyA) signal is important for mRNA stability and translatability (See pg. 19 Sec Polyadenylation signals). Makrides further teaches the more efficient polyA signal sequences to insert in mammalian expression vectors include bovine growth hormone.
Given that Picconi et al teaches a vector that can be used for gene therapy in the kidneys and Makrides teaches a polyA signal is important for mRNA stability and translatability and bGH polyA signal is one of the more efficient polyA signals for mammalian expression vectors, it would have been prima facie obvious to include a bGH polyA signal in the vector of Picconi. One would have been motivated to modify the vector in order to improve mRNA stability and translatability. There is a reasonable expectation of success because including a polyA signal in a vector is a known technique in the art.
Claims 1, 3, and 6-15 are rejected under 35 U.S.C. 103 as being unpatentable over Zou et al (Scientific Reports, 2018) as evidenced by Vector builder (VB171102-159rjs) in view of Onions et al (Diabetes, 2019) and Wang et al (Molecular Therapy, 2015), cited in IDS filed 12/10/2025.
Zou et al discloses an adenovirus vector for kidney specific expression (See Sec. Construction of the adenovirus vectors, adenovirus production, and injection). The adenovirus of Zou et al contains a NPHS2/Podocin promoter (See Sec. Construction of the adenovirus vectors, adenovirus production, and injection). The vector information sheet for the adenoviral vector of Zou et al teaches the NPHS2 promoter has podocyte specificity (See Vector Builder, Vector components). The vector of Zhou et al further comprises a SV40 polyA sequence and a Kozak sequence between the promoter and the transgene (See Vector builder, Vector map). The adenovirus of Zou et al is administered to RATS via tail vein injection
Regarding claim 1: Zou et al discloses an adenoviral vector containing an NPHS2 promoter with podocyte specificity.
Zou et al does not teach a vector comprising vascular endothelial growth factor C (VEGFC) transgene.
Onions et al teaches a mouse model (podVEGFC) which expresses VEGFC in podocytes in response to doxycycline administration (See Sec. Podocin Reverse Tetracycline-Controlled Transcriptional Activator, Tet-O-VEGFC (podVEGFC) Mice). The podVEGFC mice are used to test the effects of VEGFC overexpression on diabetic nephropathy (DN) in diabetic mouse models. Onions finds that inducing VEGFC expression prior to induction of type I diabetes by STZ injection prevents renal hypertrophy and reduces the ratio of urinary albumin to creatinine (uACR) compared to STZ control mice (See Sec. Early Glomerular VEGFC Expression Reduces the Development of DN). Additionally, Onions teaches inducing VEGFC expression during early stage STZ induced DN, reduces renal hypertrophy and uACR (See Sec. Glomerular VEGFC Intervention Reduces the Development of DN).
Given that Zou et al teaches an adenovirus vector comprising a NPHS2 promoter which is specifically expressed in podocytes and Onions et al teaches expression of VEGFC in podocytes can prevent DN and rescue early stage DN, it would have been prima facie obvious to modify the vector of Zou et al to changing transgene to a VEGFC transgene in order to express VEGFC in podocytes. One would have been motivated to make this modification because Onions et al teaches expressing VEGFC in podocytes prevents DN and can treat early-stage DN. There is a reasonable expectation of success because the vector of Zou et al has podocyte specificity.
Furthermore, Zou does not teach an AAV of serotype LK03 or 3B.
Wang et al teaches AAV LK03 and 3B can be detected in the kidney at approximately 1.E+04 (GC/ug) following IV administration (See Fig. 4).
Given that Zou et al teaches an adenovirus for expression in the kidney and Wang et al teaches AAV LK03 and 3B can be detected in kidneys, it would have been prima facie obvious to substitute the adenovirus of Zou et al with the LK03 or 3B AAV of Wang et al. One would have expected the LK03 or 3B AAVs of Wang et al to work equivocally with the adenovirus of Zou et al because Wang et al teaches AAV LK03 and 3B can be detected in kidneys. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable is considered to be obvious. See KSR International Co. V Teleflex Inc 82 USPQ2d 1385 (US2007) at page 1395.
Regarding claim 3: Following the discussion of claim 1 above, Zou et al teaches a an AAV containing a NPHS2 promoter.
Zou et al does not teach a vector comprising vascular endothelial growth factor C (VEGFC) transgene wherein the transgene comprises a polynucleotide encoding a VEGFC prepropeptide, an intermediate form of VEGFC, or a mature form of VEGFC.
Onions et al teaches expressing VEGFC in podocytes can prevent DN and can be used to treat early-stage DN.
Thus, it would have been prima facie obvious to modify the vector of Zou et al to comprise a VEGFC transgene in order to express VEGFC in podocytes (See discussion of claim 1 above).
Furthermore, it would have been prima facie obvious to express the VEGFC as a prepropeptide, intermediate form of VEGFC, or a mature form of VEGFC because any of these forms will result in expression of VEGFC. There is a motivation to express the VEGFC as a prepropeptide, intermediate form of VEGFC, or a mature form of VEGFC because any of these forms would result in expression of VEGFC. There is a reasonable expectation of success because using rAAVs to express prepropeptides, immature proteins, and mature proteins are all known techniques in the art.
Regarding claim 6: Following the discussion of claim 1 above, the adenoviral vector of Zou et al comprises a Kozak sequence between the promoter and the transgene.
Regarding claim 7: Following the discussion of claim 1 above, the adenoviral vector of Zou et al comprises an SV40 polyadenylation sequence.
Regarding claims 8-10: Zou et al teaches an adenovirus vector containing a NPHS2 promoter which drives expression in glomerular basement membrane and podocytes.
Zou et al does not teach a vector comprising vascular endothelial growth factor C (VEGFC) transgene.
Onions et al teaches a mouse model (podVEGFC) which expresses VEGFC in podocytes in response to doxycycline administration (See Sec. Podocin Reverse Tetracycline-Controlled Transcriptional Activator, Tet-O-VEGFC (podVEGFC) Mice). The podVEGFC mice are used to test the effects of VEGFC overexpression on diabetic nephropathy (DN) (reads on a diabetic kidney disease) in diabetic mouse models. Onions finds that inducing VEGFC expression prior to induction of type I diabetes by STZ injection prevents renal hypertrophy and reduces the ratio of urinary albumin to creatinine (uACR) compared to STZ control mice (See Sec. Early Glomerular VEGFC Expression Reduces the Development of DN). Additionally, Onions teaches inducing VEGFC expression during early stage STZ induced DN, reduces renal hypertrophy and uACR (See Sec. Glomerular VEGFC Intervention Reduces the Development of DN).
Given that Zou et al teaches an adenovirus vector comprising a NPHS2 promoter which is specifically expressed in podocytes and Onions et al teaches expression of VEGFC in podocytes can prevent DN and rescue early stage DN, it would have been prima facie obvious to modify the vector of Picconi et al to comprise a VEGFC transgene in order to use an effective amount of the rAAV to prevent or treat early DN (reads on treating or preventing diabetic kidney disease). One would have been motivated to make this modification because Onions et al teaches expressing VEGFC in podocytes prevents DN and can treat early-stage DN. There is a reasonable expectation of success because the adenovirus vector of Zou et al drives expression in podocytes.
Furthermore, Zou does not teach an AAV of serotype LK03 or 3B.
Wang et al teaches AAV LK03 and 3B can be detected in the kidney at approximately 1.E+04 (GC/ug) following IV administration (See Fig. 4).
Given that Zou et al teaches an AAV for expression in the kidney and Wang et al teaches AAV LK03 and 3B can be detected in kidneys, it would have been prima facie obvious to substitute the rAAV2/9 of Zou et al with the LK03 or 3B AAV of Wang et al. One would have expected the LK03 or 3B AAVs of Wang et al to work equivocally with the rAAV2/9 of Zou et al because Wang et al teaches AAV LK03 and 3B can be detected in kidneys. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable is considered to be obvious. See KSR International Co. V Teleflex Inc 82 USPQ2d 1385 (US2007) at page 1395.
Regarding claim 11: Following the discussion of claim 8 above, Zou et al teaches an AAV containing a NPHS2 promoter.
Zou et al does not teach using the vector to treat kidney disease in a human patient.
Onions et al teaches VEGFC can ameliorate albuminuria by reducing the permeability of glomerular endothelial cells (GEnC) to protein and improve DN (reads on treating a kidney disease) in experiments using human GEnCs (See Sec. Glomerular VEGFC Expression Affects VEGF Signaling and Fig. 3).
Given that Zhou et al teaches a vector which can be used to drive expression in glomeruli and Onions teaches expression of VEGFC in ameliorate albuminuria (reads on treating kidney disease) in human cells. It would have been prima facie obvious to modify the vector of Zou et al to express VEGFC in order to treat human patients with DN (reads on treating a subject that is a human patient). One would have been motivated to modify the vector in order to use the vector to treat DN in a human patient. There is a reasonable expectation of success because Onions teaches VEGFC expression improves DN in human cells.
Regarding claims 13 and 14: Following the discussion of claim 8 above, the method of Zou et al comprises injecting the rAAV into the tail vein (reads on systemic administration and an intravenous injection) of rats.
Regarding claim 15: Following the discussion of claim 8 above, Zou et al teaches an adenoviral vector that is expressed in podocytes.
Zou et al does not teach administering the rAAV via the renal artery.
Given that blood flows from the renal artery to glomeruli to be filtered, it would have been prima facie obvious to administer the vector by injecting it into the renal artery because blood flows from the renal artery to glomeruli. One would have been motivated to inject the vector into the renal artery because it is a more direct route to the glomeruli than a tail vein injection which would allow more of the vector to reach the glomeruli. There is a reasonable expectation of success because blood flows from the renal artery to glomeruli.
Claims 1 and 3-15 are rejected under 35 U.S.C. 103 as being unpatentable over Zou et al (Scientific Reports, 2018) as evidenced by Vector builder (VB171102-159rjs) in view of Onions et al (Diabetes, 2019), Wang et al (Molecular Therapy, 2015), and Otto Wilhelm et al.
The teachings of Zou et al, Onions et al, and Wang et al are set forth above.
Zou et al in view of Onions et al render claims 1, 3 and 6-15 obvious.
Regarding claim 4: Following the discussion of claim 1 above, Zou et al teaches an adenovirus vector comprising a NPHS2 promoter driving expression in podocytes.
Zou et al does not teach the adenovirus vector additionally comprises a Woodchuck hepatitis post-transcriptional regulatory element (WPRE).
Otto Wilhelm et al teaches including a WPRE sequence in a vector can increase levels of transcripts expressed by vectors (See pg. 188, last paragraph).
Given that Zou et al teaches a vector that can be used for expressing a transgene in the kidneys and Otto Wilhelm et al teaches including a WPRE sequence in a vector can increase levels of transcripts expressed by vectors, it would have been prima facie obvious to include a WPRE sequence in the vector of Zou et al in order to express higher levels of VEGFC. One would have been motivated to modify the vector in order to increase the amount of transcript expressed by the vector. There is a reasonable expectation of success because including WPRE sequences in vectors is a known technique in the art.
Regarding claim 5: Following the discussion of claim 1 above, Zou et al teaches an rAAV vector comprising a NPHS1 promoter.
Zou et al does not teach the AAV vector additionally comprises a HA tag.
Otto Wilhelm et al teaches including a HA tag in a vector improves binding of the vector with host cells (See pg. 371, second paragraph).
Given that Zou et al teaches a vector that can be used to express a transgene in podocytes and Otto Wilhelm et al teaches including a HA tag in a vector can improve binding of vectors to host cells, it would have been prima facie obvious to include a HA tag in the vector of Zou et al in order to improve binding of the vector to host cells. One would have been motivated to modify the vector in order improve binding of the vector to host cells. There is a reasonable expectation of success because including a HA tag in vectors is a known technique in the art.
Claims 1, 3, and 6-16 are rejected under 35 U.S.C. 103 as being unpatentable over Zou et al (Scientific Reports, 2018) as evidenced by Vector builder (VB171102-159rjs) in view of Onions et al (Diabetes, 2019), Wang et al (Molecular Therapy, 2015), and Makrides et al (Gene Transfer and expression in Mammalian Cells, 2003).
The teachings of Zou et al, Onions et al, and Wang et al are set forth above.
Zou et al in view of Onions et al render claims 1, 3, and 6-15 obvious.
Regarding claim 16: Following the discussion of claims 1 and 7 above, Zou et al discloses an adenoviral vector used to express a transgene in podocytes of rats. The vector of Zou et al comprises an SV40 polyA sequence.
Zou et al does not disclose a vector comprising a bGH polyadenylation sequence.
Makrides teaches a polyadenylation (polyA) signal is important for mRNA stability and translatability (See pg. 19 Sec Polyadenylation signals). Makrides further teaches the more efficient polyA signal sequences to insert in mammalian expression vectors include bovine growth hormone and SV40.
Given that Zou et al discloses a vector for expression in rats (reads on mammals) comprising a SV40 polyA signal and Makrides teaches bGH and SV40 polyA signals are among the more efficient signals to insert in mammalian expression vectors, it would have been prima facie obvious to substitute the SV40 polyA signal of Zou et al with a bGH polyA signal. One would have expected the bGH signal to work equivocally with the SV40 polyA signal in the vector of Zou et al because Makrides teaches bGH and SV40 are among the most efficient polyA signals for mammalian expression vectors. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable is considered to be obvious. See KSR International Co. V Teleflex Inc 82 USPQ2d 1385 (US2007) at page 1395.
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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/MARISOL ANN O'NEILL/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633