The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 January 20, 2026 has been entered.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.
Claims 7-8, 11-14, 17-18, 22-30, 32, 34-43, 46, 48-50, 52-53, 55-57, 59-60, 62, 64-67 are canceled. Claims 1-3, 5, 47 are withdrawn. Claims 4, 6, 9-10, 15-16, 19-21, 31, 33, 44-45, 51, 54, 58, 61, 63, 68, to nucleic acid, miRNA, Factor VIII, SEQ ID NO: 1, AAV2, are under consideration.
Priority: This application is a 371 of PCT/US18/40430, filed June 29, 2018, which claims benefit of provisional applications 62/527633, filed June 30, 2017, 62/531744, filed July 12, 2017, and 62/567905, filed October 4, 2017.
Objections and Rejections
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 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.
Claims 4, 6, 9-10, 15-16, 31, 33, 44, 54, 58, 61, 63, 68 are rejected under 35 U.S.C. 103 as being unpatentable over Wright et al. (US 20030207439; previously cited) in view of Qu II (US 20070243615, also published as EP 2781596 on IDS 10.27.21; previously cited).
Wright et al. disclose a method for purifying recombinant adeno-associated virus (rAAV) vectors comprising preparing a lysate from host cells transfected with AAV vectors and passing the lysate over various combinations of ion exchange chromatography media and/or affinity chromatography media (at least abstract, paragraphs 0017-0020, 0037). Wright et al. disclose the method comprises introducing an AAV vector into a suitable host cell; culturing the host cell to produce rAAV virions; preparing a lysate from said host cell (at least paragraphs 0106-0113, p. 11-12 claim 1); where preparing the lysate comprises harvesting cells and/or cell culture supernatant comprising rAAV-containing cells (at least paragraphs 0071-0074, 0111; instant claim 4a); concentrating the cells harvested in the cell culture medium (at least paragraph 0111; instant claim 4b); lysing the harvested cells to produce or prepare the lysate (at least paragraphs 0113-0114, p. 11-12 claim 1; instant claim 4c); treating the lysate to reduce contaminating nucleic acid (at least paragraphs 0114-0115, p. 11-12 claims 1, 9; instant claim 4d); clarifying the treated lysate by filtration (at least paragraph 0114; instant claim 4e); passing the lysate over an affinity chromatography medium to collect an eluate comprising rAAV vector particles (p. 11-12 claims 1, 3; instant claim 4f); subjecting the eluate comprising rAAV vector particles to an anion exchange chromatography medium to produce a flow-through comprising rAAV vector particles (p. 11-12 claims 1, 3; instant claim 4g); and filtering and concentrating the rAAV vector particles recovered from the various chromatography media to thereby obtain purified rAAV vector particles (at least paragraphs 0103-0104, 0121, 0124; instant claim 4i). Therefore, Wright et al. can be deemed to disclose a purification scheme similar to the method recited in instant claim 4. Wright et al. differ from the method of instant claim 4 in step 4g. Wright et al. disclose rAAV is generally recovered from an anion exchange step in the flow-through fractions (depending on the pH) (at least paragraph 0096-0097). However, instant step 4g recites that the rAAV vector binds to the anion exchange chromatography (medium) and is then eluted from the anion exchange chromatography (medium).
Wright et al. do not explicitly teach separating or reducing the numbers of empty capsids from the rAAV vector particles.
Qu II discloses the preparation of purified rAAV virions using column chromatography contains a significant amount of AAV empty capsids (at least paragraph 0005-0006). Qu II discloses methods for eliminating or reducing empty capsids from stocks of rAAV vector particles containing genetic material using column chromatography techniques (at least paragraphs 0007-0008). Qu II discloses clarified rAAV lysates are applied to an equilibrated anion exchange column and two elution buffers are used, where the lower salt eluate contains AAV empty capsids and the higher salt fractions contain AAV vector particles (at least paragraphs 0125-0128). In particular, on the anion exchange column, empty capsids can be separated from AAV vector particles using an appropriate buffer including Tris, and the salt is selected from NaCl (at least paragraph 0128). Qu II discloses that more than 90% of the AAV empty capsids can be separated away from the AAV vector particles; moreover, high recovery of AAV vector particles is readily achieved, i.e. more than 60% of the AAV vector particles can be recovered (at least paragraph 0130), including at least 75% to 90% (p. 15 claims 21-23). Qu II discloses loading a diluted clarified cell lysate containing AAV vectors onto an anion exchange column, washing the column with buffer containing 40 mM NaCl (low salt wash) and then treating the anion exchange column with buffer containing 1 M NaCl (high salt wash); where the materials washed off with the low salt wash is collected as one fraction and the materials eluted using high salt wash as a separate fraction (at least paragraph (0140-0141). Qu II discloses purified AAV vector particles are eluted when a higher concentration of sodium chloride is applied (at least paragraphs 0147, 0151, 0154). Qu II discloses separating AAV empty capsids from AAV vector particles using anion exchange chromatography with a Tris-based buffer and the salt conditions above (at least paragraphs 0154-0155). Qu II also discloses that techniques to remove empty capsids from rAAV virion preparations, such as cesium chloride gradient ultracentrifugation is labor intensive and typically result in low vector yield, and are not scalable (at least paragraph 0006).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the anion exchange chromatography conditions in Wright et al. by incorporating the anion exchange chromatography conditions suggested in Qu II in a method for purifying rAAV vector particles, where the rAAV vector particles bind to the anion exchange medium and are then eluted from the anion exchange chromatography medium with an aqueous Tris-Cl/NaCl buffer, and where the method also excludes a step of CsCl gradient ultracentrifugation, thereby arriving at the claimed method (instant claims 4, 31). The motivation to do so is given by Qu II, which discloses that empty capsids can be separated from rAAV vector particles by anion exchange chromatography under bind/elute conditions. One of ordinary skill would have further motivation to exclude a cesium chloride gradient ultracentrifugation step because it is known to be labor intensive and typically result in low vector yield (Qu II). One of ordinary skill would have a reasonable expectation of success because the cited art references disclose methods for purifying rAAV vector particles and the conditions for separating and eluting rAAV vector particles from empty capsids by anion exchange chromatography were also known. One of ordinary skill would have a further expectation of success that the method of Wright et al. and Qu II noted above recovers approximately 65-90% of the total rAAV vector particles because Qu II discloses more than 60% of the AAV vector particles can be recovered by anion exchange chromatography under bind/elute conditions (Qu II at least paragraph 0130), including at least 75% to 90% (p. 15 claims 21-23).
Regarding instant claim 6, Wright et al. disclose filtering and concentrating the rAAV vector particles recovered from the various chromatography media to thereby obtain purified rAAV vector particles, where concentration protocols include ultrafiltration/diafiltration (at least paragraph 0121).
Regarding instant claims 9-10, Wright et al. disclose lysing the harvested cells by physical means, including by a microfluidizer (at least paragraph 0076-0077).
Regarding instant claim 15, Qu II discloses diluting the clarified rAAV lysates prior to chromatography, where the lysate is diluted with sodium phosphate and NaCl buffer (at least paragraph 0141). Therefore, it would have been obvious that the treated clarified lysate in the method of Wright et a. can also be diluted by an aqueous buffered phosphate prior to purification by chromatography.
Regarding instant claim 16, as noted above, Qu II discloses diluting the clarified rAAV lysates prior to chromatography, where the lysate is diluted with sodium phosphate and NaCl buffer (at least paragraph 0141). Therefore, it would have been obvious that other crude rAAV fractions in a purification scheme can be diluted by an aqueous buffered phosphate prior to a chromatography step.
Regarding instant claim 33, as noted above, Qu II discloses washing the anion exchange column at low salt conditions with a Tris-based buffer (at least paragraphs 0125-0128, 0140-0141, 0154-0155). Therefore, it would have been obvious to arrive at a wash step using Tris-Cl/NaCl buffer.
Regarding instant claims 44, 68, Wright et al. disclose the anion exchange medium comprises a quaternary amine (at least paragraph 0095) and Qu II also discloses the anion exchange medium comprises a quaternary amine (at least paragraph 0126), including quaternary polyethyleneimine (POROS 50HQ) (instant claim 68).
Regarding instant claim 54, Wright et al. disclose the rAAV vector comprises a heterologous nucleotide sequence for a desired gene, including a gene encoding a Factor VIII protein (at least paragraph 0045).
Regarding instant claim 58, as noted above, Wright et al. disclose lysing the harvested cells to produce or prepare the lysate (at least paragraphs 0113-0114, p. 11-12 claim 1; instant claim 4c) and treating the lysate to reduce contaminating nucleic acid (at least paragraph 0115, p. 11-12 claims 1, 9; instant claim 4d); therefore, Wright et al. can be deemed to disclose performing steps (c) and (d) substantially concurrently.
Regarding instant claim 61, Wright et al. disclose the rAAV vector particles comprise an ITR sequence including from AAV-2 (at least paragraph 0038-0040).
Regarding instant claim 63, Wright et al. disclose a cell culture suitable for rAAV is HEK 293 adherent cell lines (at least paragraphs 0063, 0106).
Reply: Applicants’ amendments/remarks have been considered but they are not persuasive. The reasons for maintaining the 103 rejection are the same as previously noted and are incorporated herein.
Applicants assert that contrary to the examiner’s position that claim 4 does not actually require or limit the chromatography steps performed have to be in the order recited, claim 4 does indeed require that the chromatography steps are performed in the specified order.
Applicants’ remarks are not persuasive. Instant claim 4 is drawn to a method for purifying recombinant rAAV vector particles comprising a plurality of steps, including subjecting the nucleic acid lysate to a step (f) performing an AAV affinity column chromatography and step (g) performing an anion exchange column chromatography. However, as previously noted, instant claim 4 does not expressly recite that the chromatography steps are performed sequentially in that order. As previously noted, the instant specification discloses that the purification, production and manufacturing methods set forth herein, for example include at least 2 column chromatography steps; column chromatography steps include, for example, cation exchange chromatography, anion exchange chromatography, size exclusion chromatography, and/or AAV affinity chromatography alone or in combination and in any order (at least abstract). Therefore, the instant specification acknowledges that the combination of at least two column chromatography steps can be performed in any order.
Nevertheless, the prior art, Wright et al. disclose a purification process for rAAV vectors comprising the chromatography steps of an affinity chromatography and an anion exchange chromatography (see the 103 rejection above), which is the same order of chromatography steps recited in instant claim 4, steps f-g.
Therefore, the prior art discloses the same order of chromatography steps recited and for the same purpose of purifying rAAV vectors.
As noted in the 103 rejection, Wright et al. can be deemed to disclose a purification scheme similar to the method recited in instant claim 4. Wright et al. differ from the method of instant claim 4 at step 4g, i.e. Wright et al. do not teach the anion exchange chromatography under bind/elute conditions to recover rAAV vector particles.
Qu II discloses preparation of purified rAAV virions using column chromatography contains a significant amount of AAV empty capsids (at least paragraph 0005-0006). Qu II discloses that empty capsids can be separated from rAAV vector particles by anion exchange chromatography under bind/elute conditions.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the anion exchange chromatography conditions in Wright et al. by incorporating the anion exchange chromatography conditions suggested in Qu II in a method for purifying rAAV vector particles, where the rAAV vector particles bind to the anion exchange medium and are then eluted from the anion exchange chromatography medium with an aqueous Tris-Cl/NaCl buffer, and where the method also excludes a step of CsCl gradient ultracentrifugation, thereby arriving at the claimed method (instant claims 4, 31). The motivation to do so is given by Qu II, which discloses that empty capsids can be separated from rAAV vector particles by anion exchange chromatography under bind/elute conditions. One of ordinary skill would have further motivation to exclude a cesium chloride gradient ultracentrifugation step because it is known to be labor intensive and typically result in low vector yield (Qu II). One of ordinary skill would have a reasonable expectation of success because the cited art references disclose methods for purifying rAAV vector particles and the conditions for separating and eluting rAAV vector particles from empty capsids by anion exchange chromatography were also known. One of ordinary skill would have a further expectation of success that the method of Wright et al. and Qu II noted above recovers approximately 65-90% of the total rAAV vector particles because Qu II discloses more than 60% of the AAV vector particles can be recovered by anion exchange chromatography under bind/elute conditions (Qu II at least paragraph 0130), including at least 75% to 90% (p. 15 claims 21-23).
Applicants assert that one of skill would not have been motivated to substitute the flow-through anion exchange step Wright et al. with a bind-and-elute anion exchange chromatography step of Qu II because Wright et al. teach that the flow-through anion exchange step is necessary to reduce contaminating proteins and nucleic acids when starting with a lysate.
Applicants’ remarks are not persuasive. As noted in the 103 rejection, Qu II discloses that with bind and elute conditions on anion exchange chromatography, empty capsids can be separated from AAV vector particles using an appropriate buffer including Tris, and the salt is selected from NaCl (at least paragraph 0128). Qu II discloses that more than 90% of the AAV empty capsids can be separated away from the AAV vector particles; moreover, high recovery of AAV vector particles is readily achieved, i.e. more than 60% of the AAV vector particles can be recovered (at least paragraph 0130), including at least 75% to 90% (p. 15 claims 21-23).
Therefore, one of ordinary skill would have reasonable motivation to incorporate the anion exchange chromatography bind/elute conditions disclosed in Qu II for the anion exchange chromatography conditions in the method of Wright et al. because the bind/elute conditions for anion exchange chromatography separates more than 90% empty capsids from AAV vector particles and high recovery of AAV vector particles is readily achieved, including at least 90%.
Regarding Applicants’ remarks that Qu II discloses additional purification steps with the anion exchange chromatography bind/elute conditions, i.e. first performing a cation exchange step, the remarks are not persuasive. Even if Qu II discloses an additional chromatography step before the anion exchange chromatography bind/elute conditions, it still does not teach away from Qu II disclosing that with bind and elute conditions on anion exchange chromatography, empty capsids can be separated from AAV vector particles using an appropriate buffer including Tris, and the salt is selected from NaCl (at least paragraph 0128) and that more than 90% of the AAV empty capsids can be separated away from the AAV vector particles; moreover, high recovery of AAV vector particles is readily achieved, i.e. more than 60% of the AAV vector particles can be recovered (at least paragraph 0130), including at least 75% to 90% (p. 15 claims 21-23).
Regarding Applicants’ remarks that Qu II disclose anion exchange chromatography with AAV vectors in CsCl-gradient pre-purified and mixed samples, the remarks are not persuasive. As previously noted, when Qu II discloses that the empty capsids and rAAV vector particles are separated from CsCl purified samples, a clear separation as observed for the CsCl-gradient pre-purified and mixed samples was not obtained, although the two particle types remained distinguishable i.e. partial but incomplete separation of empty capsids and AAV vector particles was observed (paragraph 0153). Therefore, Qu II further demonstrates that a step of cesium chloride gradient ultracentrifugation is not always desired.
Qu II discloses that techniques to remove empty capsids from rAAV virion preparations, such as cesium chloride gradient ultracentrifugation is labor intensive and typically result in low vector yield, and are not scalable (at least paragraph 0006).
In this instance, Qu II discloses high recovery of AAV vector particles is achieved by anionic exchange chromatography without CsCl gradient ultracentrifugation, i.e. where at least 75%, 90% recovery of AAV vector particles (at least p. 15 claims 21-23).
Therefore, the prior art (Qu II) fairly discloses high recovery of AAV vector particles can be achieved without CsCl gradient ultracentrifugation.
Applicants assert that claim 4, step (i) specifies that the method recovers approximately 60-90% of total rAAV vector particles from the harvest produced in (a) or said concentrated harvest produced in (b). Applicants assert that in other words, the claim specifies that the level of recovery refers to the result of steps (a) to (i).
Applicants’ remarks are not persuasive because as noted above, the prior art discloses the same combination of chromatography steps recited for the same purpose of purifying rAAV vectors and further discloses that more than 60% of the AAV vector particles can be recovered by anion exchange chromatography under bind/elute conditions (Qu II at least paragraph 0130), including at least 75% to 90% (Qu II p. 15 claims 21-23).
Applicants assert that Qu II is silent with respect to an affinity purification step prior to anion exchange.
Applicants’ remarks are not persuasive. The deficiency of Qu II to not expressly teach an affinity purification step prior to anion exchange is remedied by Wright et al., which disclose performing an affinity chromatography step prior to an anion exchange step.
Applicants assert that the level of recovery disclosed in Qu II, including at least 75% to 90% (p. 15 claims 21-23) refers to the level of recovery after a single anion exchange step from an AAV preparation comprising AAV vector particles. Applicants assert that nowhere does Qu II teach or suggest that approximately 60-95% of the total rAAV vector particles are recovered after harvest and lysis, let alone after harvest, lysis, affinity, anion exchange, and filtering. Applicants assert that at most Qu II discloses the recovery after a single anion exchange (paragraphs 0126-0130) or after a cation exchange step followed by anion exchange (paragraphs 0126-0130).
Applicants’ remarks are not persuasive. As acknowledged by Applicants, Qu II discloses a recovery level including at least 75% to 90% after at least an anion exchange step (see also Qu II paragraph 0130, p. 15 claims 21-23). Therefore, one of ordinary skill would have a reasonable expectation of success that the AAV vector particles recovered by anion exchange chromatography under bind/elute conditions as disclosed in Qu II will have a recovery level including at least 75% to 90% when combined with other known purification steps, including the purification and chromatography steps of Wright et al.
Therefore, Applicants’ remarks that the level of recovery disclosed in Qu II cannot be considered as evidence of a reasonable expectation of success are not persuasive.
See also the reasons noted on at least p. 8-12 of the December 24, 2024 non-final office action.
Claims 4, 45 are rejected under 35 U.S.C. 103 as being unpatentable over Wright et al. (US 20030207439; previously cited) in view of Qu II (US 20070243615, also published as EP 2781596 on IDS 10.27.21; previously cited) and Qu et al. (2015 Current Pharmaceutical Biotechnology 16: 684-695; IDS 12.28.21, previously cited). The teachings of Wright et al. in view of Qu II are noted above. Wright et al. disclose the rAAV obtained after ion exchange and/or affinity column chromatography can be subjected to a polishing step, an additional ion exchange or affinity step (at least paragraph 0097). Wright et al. disclose providing large-scale purification of rAAV (at least abstract, paragraph 0017). Wright et al. do not teach size-exclusion chromatography (optional step (h)).
Qu et al. disclose strategies for purification rAAV vectors. Qu et al. disclose SEC (size-exclusion chromatograph), also known as gel-filtration chromatography, is a method to separate large biomolecules by their size or weight in solution (p. 686). Qu et al. disclose SEC technology can be used as a “polishing” step in purifying rAAV vectors (p. 686).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the references and further subject the eluate comprising rAAV vectors obtained after anion exchange chromatography in the method of Wright et al. in view of Qu II to the SEC chromatography of Qu et al. (instant claim 4h). The motivation to do so is given by the prior art. Wright et al. disclose a polishing step after an ion exchange and/or affinity column chromatography. It is disclosed that SEC chromatography can be used to purify rAAV vectors in a polishing (or purification) step. Therefore, one of ordinary skill would have reasonable motivation to combine the teachings of the prior art as noted above to arrive at the claimed method. One of ordinary skill would have a reasonable expectation of success because methods for purifying rAAV vectors were known and chromatography media used to purify biomolecules were also well known as disclosed in the cited prior art.
Regarding instant claim 45, Qu et al. disclose Superdex 200 is able to largely exclude rAAV viral particles (p. 686); therefore, Qu et al. can be deemed to disclose the recited range.
Reply: Applicants’ remarks have been considered but they are not persuasive.
Regarding Applicants’ remarks that Qu et al. provide further evidence that it would not be obvious to substitute the flow-through anion exchange step Wright et al. with a bind-and-elute anion exchange chromatography step of Qu II because Wright et al. teach that the flow-through anion exchange step is necessary to reduce contaminating proteins and nucleic acids when starting with a lysate, the remarks are not persuasive. The reasons for maintaining Wright et al. and Qu II are the same as noted above.
Regarding Applicants’ remarks that Qu et al. explicitly provides motivation to include a CsCl ultracentrifugation step and that processes comprising such steps are expressly excluded from the instant claims, the remarks are not persuasive.
As previously noted, it is known that the omission of an element and its function is obvious if the function of the element is not desired or required. MPEP 2144.04.
In this instance, Wright et al. disclose that CsCl density gradient methods are not suitable for producing commercial scale quantities of rAAV (at least paragraph 0013); therefore, Wright et al. can be deemed to disclose that a step of cesium chloride gradient ultracentrifugation is not always desired.
While Qu II discloses that rAAV virions can be purified from a host cell using a variety of conventional purification methods, including CsCl gradients (paragraph 0119), as previously noted by Applicants, Qu II has also disclosed that techniques to remove empty capsids from rAAV virion preparations, such as cesium chloride gradient ultracentrifugation is labor intensive and typically result in low vector yield, and are not scalable (at least paragraph 0006).
Further, Qu II discloses that high recovery of AAV vector particles by anionic exchange chromatography without CsCl gradient ultracentrifugation, i.e. where at least 75%, 90% recovery of AAV vector particles (at least p. 15 claims 21-23).
Therefore, the prior art (Qu II) fairly discloses high recovery of AAV vector particles can be achieved without CsCl gradient ultracentrifugation.
Regarding Applicants’ remarks on Qu et al., the remarks are not persuasive. Qu et al. also disclose that CsCl ultracentrifugation is time-consuming and is unsuited for the large scale rAAV downstream processing (p. 6685).
Additionally, as previously noted, when Qu II discloses that the empty capsids and rAAV vector particles are separated from CsCl purified samples, a clear separation as observed for the CsCl-gradient pre-purified and mixed samples was not obtained, although the two particle types remained distinguishable i.e. partial but incomplete separation of empty capsids and AAV vector particles was observed (paragraph 0153). Therefore, Qu II further demonstrates that a step of cesium chloride gradient ultracentrifugation is not always desired.
In this instance, the prior art disclose other purification techniques or methods that successfully purify rAAV vector particles and that do not include cesium chloride ultracentrifugation. See the teachings of Wright et al. and Qu II noted above. Therefore, a step of cesium chloride gradient ultracentrifugation is not always desired.
Therefore, one of ordinary skill would have further motivation to exclude a cesium chloride gradient ultracentrifugation step because it is known to be labor intensive and typically result in low vector yield.
For at least these reasons, the 103 rejection is maintained.
Claims 4, 19, 51 are rejected under 35 U.S.C. 103 as being unpatentable over Wright et al. (US 20030207439; previously cited) in view of Qu II (US 20070243615, also published as EP 2781596 on IDS 10.27.21; previously cited) and Wright II (US 20130072548; IDS 12.27.19, previously cited). The teachings of Wright et al. in view of Qu II are noted above. Wright et al. do not explicitly teach formulating the purified rAAV vector particles in a surfactant.
Wright II also discloses methods for preparing highly purified rAAV vector formulations comprising purification over anion exchange medium (at least paragraphs 0010, 0052-0062). Wright II discloses after purification by ion exchange chromatography and concentration, the purified rAAV vector particles are formulated in surfactant (at least paragraph 0010). The addition of surfactant prevents binding of the vector to an injection device (at least paragraph 0075).
Regarding instant claim 19, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate a surfactant as suggested in Wright II to the purified rAAV vector particles recovered after anion exchange chromatography and filtration in the method of Wright et al. in view of Qu II because Wright II discloses addition of surfactant prevents binding of the rAAV vector particles to an injection device. One of ordinary skill would have a reasonable expectation of success because the cited art references disclose methods for purifying rAAV vector particles and methods for formulating the rAAV vector particles into compositions.
Regarding instant claim 51, Wright II discloses that the rAAV vector comprises a heterologous nucleotide sequence for a desired gene, including miRNAs (at least paragraph 0014).
Reply: Applicants’ remarks have been considered but they are not persuasive. The reasons for maintaining Wright et al. and Qu II are the same as noted above.
Regarding Applicants’ remarks that Wright II explicitly provides motivation to include a CsCl ultracentrifugation step as part of a “critical core sequence of column chromatography”, the remarks are not persuasive for the reasons previously noted.
As previously noted, Wright II restricts or limits how a cesium chloride gradient ultracentrifugation step is to be applied in a purification scheme for rAAV vector particles, i.e. it has to be part of a critical order of steps including column chromatography followed by tangential flow filtration and then followed by gradient ultracentrifugation, for large-scale purification (at least paragraphs 0020, 0070).
In this instance, the prior art disclose other purification techniques or methods that successfully purify rAAV vector particles and that do not include cesium chloride ultracentrifugation. See the teachings of Wright et al. and Qu II noted above. Therefore, a step of cesium chloride gradient ultracentrifugation is not always desired.
Additionally, Wright II is not being relied upon for the teaching of the critical “core” sequence of steps. Wright II is being relied upon for the teaching that purified rAAV vector particles are formulated in surfactant (at least paragraph 0010) because the addition of surfactant prevents binding of the vector to an injection device (at least paragraph 0075). See the 103 rejection at least instant claim 19.
Further, in this instance, Qu II has also disclosed that techniques to remove empty capsids from rAAV virion preparations, such as cesium chloride gradient ultracentrifugation is labor intensive and typically result in low vector yield (see above).
Therefore, one of ordinary skill would have further motivation to exclude a cesium chloride gradient ultracentrifugation step because it is known to be labor intensive and typically result in low vector yield.
For at least these reasons, the 103 rejection is maintained.
Claims 4, 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Wright et al. (US 20030207439; previously cited) in view of Qu II (US 20070243615, also published as EP 2781596 on IDS 10.27.21, previously cited) and Zhou et al. (2011 Journal of Virological Methods 173: 99-107; IDS 08.17.22, previously cited). The teachings of Wright et al. and Qu II are noted above. The cited art references do not teach that the anionic exchange chromatography comprises PEG modulated chromatography.
Zhou et al. disclose PEG modulated chromatography for purification of AAV vectors. Zhou et al. disclose that inclusion of PEG in chromatography buffers modulated rAAV9 elution profiles in a manner that resulted in significantly improved resin binding capacity, vector purity and yield (at least abstract). Zhou et al. disclose both anion and cation resins are evaluated for rAAV9 (at least section 2.2). Zhou et al. disclose PEG-modulated chromatography is predicted to be of value in developing purification processes for other rAAV serotypes (p. 106).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to further incorporate PEG-modulated column chromatography with the anion exchange column chromatography disclosed in the method for purifying rAAV vector particles of Wright et al. and Qu II noted above (instant claim 20). The motivation to do so is given by Zhou et al., which disclose inclusion of PEG in ion exchange chromatography improves binding capacity, vector purity, and yield. One of ordinary skill would have a reasonable expectation of success because the cited art references disclose methods for purifying rAAV vector particles and it was known PEG-modulated column chromatography improves resin binding capacity.
Regarding instant claim 21, Zhou et al. disclose development of PEG-modulated chromatography, including washing steps with a PEG solution (at least p. 101).
Reply: Applicants’ remarks have been considered but they are not persuasive. The reasons for maintaining Wright et al. and Qu II are the same as noted above.
Regarding Applicants’ remarks that Zhou et al. do not teach or suggest affinity chromatography followed by a bind and elute anion exchange and the specific exclusion of a CsCl ultracentrifugation, the remarks are not persuasive. Zhou et al. is cited with Wright et al. and Qu II, which disclose an affinity chromatography step followed by an anion exchange chromatography (Wright et al.), where the anion exchange chromatography is under bind/elute conditions (Qu II), and where a CsCl ultracentrifugation step is not included (Wright et al.; Qu II).
For at least these reasons, the 103 rejection is maintained.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 4, 6, 9-10, 15-16, 19-21, 31, 33, 44-45, 51, 54, 58, 61, 63, 68 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 10328145 (‘145) in view of Wright et al. (supra), Qu II (supra), Qu et al. (supra), and/or Zhou et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claim 4 and the ‘145 patent claim 1 are drawn to a method for purifying rAAV vectors comprising harvesting cells and/or cell culture supernatant comprising rAAV-containing cells; concentrating the cells harvested in the cell culture medium; lysing the harvested cells to produce or prepare the lysate; filtering the lysate; subjecting the lysate comprising rAAV vector particles to an anion exchange chromatography medium; and filtering and concentrating the rAAV vector particles recovered from the chromatography media to thereby obtain purified rAAV vector particles. The ‘145 patent specification discloses that the ion exchange chromatography recited in claim 1 is anion exchange chromatography. The ‘145 patent claim differs from the instant claim by not explicitly reciting treating the lysate to further reduce nucleic acid contaminants or an affinity chromatography media step. However, in view of the teachings of Wright et al. noted above, it would have been obvious to one of ordinary skill to further incorporate treating the lysate to further reduce nucleic acid contaminants and an affinity chromatography media step prior to the anion exchange chromatography media step as disclosed in Wright et al. One of ordinary skill would have a reasonable expectation of success because these were steps recognized in purification of rAAV vectors.
The ‘145 patent claim also differs from the instant claim by reciting a gradient ultracentrifugation step. However, in view of the teachings of Wright et al. and/or Qu II noted above, it would have been obvious for one of ordinary skill to exclude the gradient ultracentrifugation step recited because it is known to be labor intensive and typically result in low vector yield.
Regarding the instant dependent claims, if any of the recited elements and/or components are not expressly recited in the ‘145 patent claims, it would have been obvious to incorporate the noted element(s) and/or component(s) in view of the teachings of Wright et al., Qu II, Qu et al., and/or Zhou et al. noted above.
Reply: Applicants’ remarks regarding the nonstatutory double patenting rejection over the ‘145 patent have been considered but they are not persuasive. The nonstatutory double patenting rejection over the ‘145 patent is maintained for the reasons noted above.
Claims 4, 6, 9-10, 15-16, 19-21, 31, 33, 44-45, 51, 54, 58, 61, 63, 68 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, , 8-21 of U.S. Patent No. 9408904 (‘904) in view of Wright et al. (supra), Qu II (supra), Qu et al. (supra), and/or Zhou et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claim 4 and the ‘904 patent claim 1 are drawn to a method for purifying rAAV vectors comprising harvesting cells and/or cell culture supernatant comprising rAAV-containing cells; concentrating the cells harvested in the cell culture medium; lysing the harvested cells to produce or prepare the lysate; filtering the lysate; subjecting the lysate comprising rAAV vector particles to an anion exchange chromatography medium; and filtering and concentrating the rAAV vector particles recovered from the chromatography media to thereby obtain purified rAAV vector particles. The ‘904 patent specification discloses that the ion exchange chromatography recited in claim 1 is anion exchange chromatography. The ‘904 patent claims differ from the instant claim by not explicitly reciting treating the lysate to further reduce nucleic acid contaminants or an affinity chromatography media step. However, in view of the teachings of Wright et al. noted above, it would have been obvious to one of ordinary skill to further incorporate treating the lysate to further reduce nucleic acid contaminants and an affinity chromatography media step prior to the anion exchange chromatography media step as disclosed in Wright et al. One of ordinary skill would have a reasonable expectation of success because these were steps recognized in purification of rAAV vectors.
The ‘904 patent claim also differs from the instant claim by reciting a gradient ultracentrifugation step. However, in view of the teachings of Wright et al. and/or Qu II noted above, it would have been obvious for one of ordinary skill to exclude the gradient ultracentrifugation step recited because it is known to be labor intensive and typically result in low vector yield.
Regarding the instant dependent claims, if any of the recited elements and/or components are not expressly recited in the ‘904 patent claims, it would have been obvious to incorporate the noted element(s) and/or component(s) in view of the teachings of Wright et al., Qu II, Qu et al., and/or Zhou et al. noted above.
Reply: Applicants’ remarks regarding the nonstatutory double patenting rejection over the ‘904 patent have been considered but they are not persuasive. The nonstatutory double patenting rejection over the ‘904 patent is maintained for the reasons noted above.
Claims 4, 6, 9-10, 15-16, 19-21, 31, 33, 44-45, 51, 54, 58, 61, 63, 68 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 11878056 (‘056) in view of Wright et al. (supra), Qu II (supra), Qu et al. (supra), and/or Zhou et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claim 4 and the ‘056 patent claim 15 are drawn to a method for purifying rAAV vectors comprising harvesting cells and/or cell culture supernatant comprising rAAV-containing cells; concentrating the cells harvested in the cell culture medium; lysing the harvested cells to produce or prepare the lysate; filtering the lysate; subjecting the lysate comprising rAAV vector particles to an anion exchange chromatography medium; and filtering and concentrating the rAAV vector particles recovered from the chromatography media to thereby obtain purified rAAV vector particles. The ‘056 patent specification discloses that the ion exchange chromatography recited in claim 1 is anion exchange chromatography. The ‘056 patent claim differs from the instant claim by not explicitly reciting treating the lysate to further reduce nucleic acid contaminants or an affinity chromatography media step. However, in view of the teachings of Wright et al. noted above, it would have been obvious to one of ordinary skill to further incorporate treating the lysate to further reduce nucleic acid contaminants and an affinity chromatography media step prior to the anion exchange chromatography media step as disclosed in Wright et al. One of ordinary skill would have a reasonable expectation of success because these were steps recognized in purification of rAAV vectors.
The ‘056 patent claim also differs from the instant claim by reciting a gradient ultracentrifugation step. However, in view of the teachings of Wright et al. and/or Qu II noted above, it would have been obvious for one of ordinary skill to exclude the gradient ultracentrifugation step recited because it is known to be labor intensive and typically result in low vector yield.
Regarding the instant dependent claims, if any of the recited elements and/or components are not expressly recited in the ‘056 patent claims, it would have been obvious to incorporate the noted element(s) and/or component(s) in view of the teachings of Wright et al., Qu II, Qu et al., and/or Zhou et al. noted above.
Reply: Applicants’ remarks regarding the nonstatutory double patenting rejection over the ’056 patent have been considered but they are not persuasive. The nonstatutory double patenting rejection over the ‘056 patent is maintained for the reasons noted above.
Claims 4, 6, 9-10, 15-16, 19-21, 31, 33, 44-45, 51, 54, 58, 61, 63, 68 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 7261544 (‘544) in view of Wright et al. (supra), Qu II (supra), Qu et al. (supra), Wright (supra), and/or Zhou et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claim 4 and the ‘544 patent claim 1 are drawn to a method for purifying rAAV vectors comprising harvesting cells and/or cell culture supernatant comprising rAAV-containing cells; concentrating the cells harvested in the cell culture medium; lysing the harvested cells to produce or prepare the lysate; filtering the lysate; subjecting the lysate comprising rAAV vector particles to an anion exchange chromatography medium under bind/elute conditions; and filtering and concentrating the rAAV vector particles recovered from the chromatography media to thereby obtain purified rAAV vector particles. Instant claim 4 excludes a cesium chloride gradient ultracentrifugation step and the ‘544 patent claim does not recite a cesium chloride gradient ultracentrifugation step. The ‘544 patent claims differ from the instant claim by not explicitly reciting treating the lysate to further reduce nucleic acid contaminants, an affinity chromatography media step, or filtering steps. However, in view of the teachings of Wright et al. noted above, it would have been obvious to one of ordinary skill to further incorporate treating the lysate to further reduce nucleic acid contaminants, an affinity chromatography media step prior to the anion exchange chromatography media step, and filtering steps as disclosed in Wright et al. One of ordinary skill would have a reasonable expectation of success because these were steps recognized in purification of rAAV vectors.
Regarding the instant dependent claims, if any of the recited elements and/or components are not expressly recited in the ‘544 patent claims, it would have been obvious to incorporate the noted element(s) and/or component(s) in view of the teachings of Wright et al., Qu II, Qu et al., Wright II, and/or Zhou et al. noted above.
Reply: Applicants’ remarks regarding the nonstatutory double patenting rejection over the ’544 patent have been considered but they are not persuasive. The nonstatutory double patenting rejection over the ‘544 patent is maintained for the reasons noted above.
Claims 4, 6, 9-10, 15-16, 19-21, 31, 33, 44-45, 51, 54, 58, 61, 63, 68 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 8137948 (‘948) in view of Wright et al. (supra), Qu II (supra), Qu et al. (supra), Wright II (supra), and/or Zhou et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claim 4 and the ‘948 patent claim 1 are drawn to a method for purifying rAAV vectors comprising subjecting a rAAV preparation to anion exchange chromatography media under bind/elute conditions. Instant claim 4 excludes a cesium chloride gradient ultracentrifugation step and the ‘948 patent claim does not recite a cesium chloride gradient ultracentrifugation step. The ‘948 patent claim differs from the instant claim by not explicitly reciting harvesting cells comprising rAAV vector particles, preparing a lysate, treating the lysate to further reduce nucleic acid contaminants, an affinity chromatography media step, and/or filtering steps. However, in view of the teachings of Wright et al. noted above, it would have been obvious to one of ordinary skill to further incorporate harvesting cells containing rAAV to prepare a lysate, treating the lysate to further reduce nucleic acid contaminants, an affinity chromatography media step prior to the anion exchange chromatography media step, and filtering steps as disclosed in Wright et al. One of ordinary skill would have a reasonable expectation of success because these were steps recognized in purification of rAAV vectors.
Regarding the instant dependent claims, if any of the recited elements and/or components are not expressly recited in the ‘948 patent claims, it would have been obvious to incorporate the noted element(s) and/or component(s) in view of the teachings of Wright et al., Qu II, Qu et al., Wright II, and/or Zhou et al. noted above.
Reply: Applicants’ remarks regarding the nonstatutory double patenting rejection over the ’948 patent have been considered but they are not persuasive. The nonstatutory double patenting rejection over the ‘948 patent is maintained for the reasons noted above.
Claims 4, 6, 9-10, 15-16, 19-21, 31, 33, 44-45, 51, 54, 58, 61, 63, 68 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 9528126 (‘126) in view of Wright et al. (supra), Qu II (supra), Qu et al. (supra), Wu II (supra), and/or Zhou et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claim 4 and the ‘126 patent claim 1 are drawn to a method for purifying rAAV vectors comprising subjecting a rAAV preparation to anion exchange chromatography media under bind/elute conditions. Instant claim 4 excludes a cesium chloride gradient ultracentrifugation step and the ‘126 patent claim does not recite a cesium chloride gradient ultracentrifugation step. The ‘126 patent claim differs from the instant claim by not explicitly reciting harvesting cells comprising rAAV vector particles, preparing a lysate, treating the lysate to further reduce nucleic acid contaminants, an affinity chromatography media step, and/or filtering steps. However, in view of the teachings of Wright et al. noted above, it would have been obvious to one of ordinary skill to further incorporate harvesting cells containing rAAV to prepare a lysate, treating the lysate to further reduce nucleic acid contaminants, an affinity chromatography media step prior to the anion exchange chromatography media step, and filtering steps as disclosed in Wright et al. One of ordinary skill would have a reasonable expectation of success because these were steps recognized in purification of rAAV vectors.
Regarding the instant dependent claims, if any of the recited elements and/or components are not expressly recited in the ‘126 patent claims, it would have been obvious to incorporate the noted element(s) and/or component(s) in view of the teachings of Wright et al., Qu II, Qu et al., Wu II, and/or Zhou et al. noted above.
Reply: Applicants’ remarks regarding the nonstatutory double patenting rejection over the ’126 patent have been considered but they are not persuasive. The nonstatutory double patenting rejection over the ‘126 patent is maintained for the reasons noted above.
Claims 4, 6, 9-10, 15-16, 19-21, 31, 33, 44-45, 51, 54, 58, 61, 63, 68 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 11261463 (‘463) in view of Wright et al. (supra), Qu II (supra), Qu et al. (supra), and/or Zhou et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claim 4 and the ‘463 patent claim 1 are drawn to a method for purifying rAAV vectors comprising subjecting a rAAV preparation to anion exchange chromatography media under bind/elute conditions. Instant claim 4 excludes a cesium chloride gradient ultracentrifugation step and the ‘463 patent claim does not recite a cesium chloride gradient ultracentrifugation step. The ‘463 patent claim differs from the instant claim by not explicitly reciting harvesting cells comprising rAAV vector particles, preparing a lysate, treating the lysate to further reduce nucleic acid contaminants, an affinity chromatography media step, and/or filtering steps. However, in view of the teachings of Wright et al. noted above, it would have been obvious to one of ordinary skill to further incorporate harvesting cells containing rAAV to prepare a lysate, treating the lysate to further reduce nucleic acid contaminants, an affinity chromatography media step prior to the anion exchange chromatography media step, and filtering steps as disclosed in Wright et al. One of ordinary skill would have a reasonable expectation of success because these were steps recognized in purification of rAAV vectors.
Regarding the instant dependent claims, if any of the recited elements and/or components are not expressly recited in the ‘463 patent claims, it would have been obvious to incorporate the noted element(s) and/or component(s) in view of the teachings of Wright et al., Qu II, Qu et al., Wu II, and/or Zhou et al. noted above.
Reply: Applicants’ remarks regarding the nonstatutory double patenting rejection over the ’463 patent have been considered but they are not persuasive. The nonstatutory double patenting rejection over the ‘463 patent is maintained for the reasons noted above.
Claims 4, 6, 9-10, 15-16, 19-21, 31, 33, 44-45, 51, 54, 58, 61, 63, 68 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-47 of U.S. Patent No. 11702639 (‘639) in view of Wright et al. (supra), Qu II (supra), Qu et al. (supra), and/or Zhou et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claim 4 and the ‘639 patent claim 1 are drawn to a method for purifying rAAV vectors comprising harvesting cells and/or cell culture supernatant comprising rAAV-containing cells; concentrating the cells harvested in the cell culture medium; lysing the harvested cells to produce or prepare the lysate; treating the lysate to reduce nucleic acid contaminants; filtering the lysate; subjecting the lysate comprising rAAV vector particles to an anion exchange chromatography medium under bind/elute conditions; and filtering and concentrating the rAAV vector particles recovered from the chromatography media to thereby obtain purified rAAV vector particles. Instant claim 4 excludes a cesium chloride gradient ultracentrifugation step and the ‘639 patent claim 1 does not recite a cesium chloride gradient ultracentrifugation step. The ‘639 patent claim differs from the instant claim by not explicitly reciting an affinity chromatography media step. However, in view of the teachings of Wright et al. noted above, it would have been obvious to one of ordinary skill to further incorporate an affinity chromatography media step prior to the anion exchange chromatography media step as disclosed in Wright et al. One of ordinary skill would have a reasonable expectation of success because these were steps recognized in purification of rAAV vectors.
Regarding the instant dependent claims, if any of the recited elements and/or components are not expressly recited in the ‘639 patent claims, it would have been obvious to incorporate the noted element(s) and/or component(s) in view of the teachings of Wright et al., Qu II, Qu et al., and/or Zhou et al. noted above.
Reply: Applicants’ remarks regarding the nonstatutory double patenting rejection over the ’639 patent have been considered but they are not persuasive. The nonstatutory double patenting rejection over the ‘639 patent is maintained for the reasons noted above.
No claim is allowed.
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/Marsha Tsay/Primary Examiner, Art Unit 1656