DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-4, 6-15, 17, and 27-40 were previously pending.
Receipt is acknowledged of the Amendments to the claims submitted on 16 July 2026. Claims 1-3, 12-13, 27, 33, 35, and 37 are amended. Claims 32 and 34 are cancelled. Claims 41-42 are newly added.
Therefore, claims 1-4, 6-15, 17, 27-31, 33, and 35-42 are pending and under examination in the present Official Action. Claims 1 and 27 are independent claims.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2021/045677, filed 12 August 2021, which claims priority to United States Provisional Application No. 63065225, filed 13 August 2020. Acknowledgment is made of applicant’s claim for priority.
The earliest possible priority for the instant application is 13 August 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 16 July 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The Examiner thanks Applicant for the submission of replacement drawings on 16 July 2026. The objection to the drawings is withdrawn and the drawings submitted on 16 July 2026 are accepted by the Examiner.
Withdrawn Rejections in view of Applicant’s Amendments/Arguments
Claim Rejections - 35 USC § 112
The rejection of claims 2-4, 6-9, 12-13, and 28-29 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in view of Applicant’s amendments to the claims. Applicant has amended claims 2 and 13 to correct previously-raised issues of indefiniteness.
Maintained Rejections in view of Applicant’s Amendments/ArgumentsClaim Rejections - 35 USC § 103
Claims 1-4, 6-15, 17, 27-29, 33, and 35-38 remain rejected and new claims 41-42 are newly rejected under 35 U.S.C. 103 as being unpatentable over US 20170073702, published: 16 March, 2017, hereinafter “Oxford” in view of Ausubel, et al. BioProcess international 10.2 (2012): 32, hereinafter “Ausubel”, and Appel, et al. Best Practices in Nucleic Acid Removal from Vaccine Processes, Merck Millipore, 2013, hereinafter “Appel”, as evidenced by Millipore Q&A (https://www.sigmaaldrich.com/US/en/technical-documents/technical-article/protein-biology/protein-lysis-and-extraction/answers-to-questions-about-benzonase-nuclease?srsltid=AfmBOopviBYWcaub51ZC2MEnSwcPZrqREOJNX3sXi2jvibVS1nmK-ZtJ), Serratia nuclease Wikipedia (https://en.wikipedia.org/wiki/Serratia_marcescens_nuclease), and Cell Biolabs FAQ (https://www.cellbiolabs.com/faq/viral-expression-faq/retroviral-quantitation#:~:text=A:%20Viral%20titers%20are%20represented,be%20calculated%20from%20physical%20titer) all accessed: 10 April, 2026. This rejection has been withdrawn with respect to pending claims 30-31, and 39-40 in view of Applicant’s arguments (discussed below), withdrawn with respect to claims 32 and 34 which were canceled by amendment, and modified as necessitated by Applicant’s amendments to the claims.
Regarding claim 1, Oxford teaches methods for producing retroviral or lentiviral vector formulations comprising a filter sterilization step (Oxford, Abstract). In the methods of Oxford, the last step in the process is a step of concentration (Oxford, Figure 1, claim 45). Oxford also teaches a step of nuclease treatment (Benzonase®) in the method (Oxford, Figure 1). The nuclease treatment exemplified in Figure 1 of Oxford is in a step which occurs after a step of clarifying and before a step of IEX chromatography and the filter sterilization of Oxford utilized a 0.2μm filter (Oxford, Figure 1). Oxford teaches that tangential flow filtration, a type of ultrafiltration, is widely used in the bioprocessing industry for cell harvesting, clarification, purification and concentration and discloses a molecular weight cutoff for the tangential flow filtration of 100 to 1000 kDa as appropriate for retroviral vectors (Oxford, [0201]).
Oxford does not explicitly teach a nuclease treatment step after a step of filter sterilization.
However, Oxford does suggest to use multiple nuclease treatment steps in the method (Oxford, [0037]-[0040]). The final step in the process of Oxford is an ultrafiltration concentration step which occurs after a filter sterilization step (Oxford, Figure 1).
Appel teaches that ultrafiltration is an effective method for the removal of residual nucleic acids and Benzonase® enzyme (Appel, whole document). Thus, a person having ordinary skill in the art would have understood from the teachings of Appel that, so long as a method for producing viral particles ends with an ultrafiltration concentration step, they need not worry about the precise timing of Benzonase® treatment because said Benzonase® will be removed by said final ultrafiltration concentration step.
Accordingly, precisely where the multiple nuclease treatment steps occur in the method of Oxford would be an obvious matter of design choice to a person having ordinary skill in the art which would not have modified the operation of the method of Oxford. See In re Japikse, 181 F.2d 1019, 86 USPQ 70 (CCPA 1950) (Claims to a hydraulic power press which read on the prior art except with regard to the position of the starting switch were held unpatentable because shifting the position of the starting switch would not have modified the operation of the device.); and In re Kuhle, 526 F.2d 553, 188 USPQ 7 (CCPA 1975) (the particular placement of a contact in a conductivity measuring device was held to be an obvious matter of design choice).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have performed multiple nuclease treatment steps in the method of Oxford wherein one of those steps occurs after filter sterilization but before ultrafiltration mediated concentration and to have arrived at the invention claimed in instant claim 1 with a reasonable expectation of success because Oxford suggests to perform multiple nuclease treatment steps and Appel teaches that the final ultrafiltration mediated concentration step of Oxford is sufficient to remove any residual nuclease rendering the exact timing of nuclease treatment prior to the final concentration step an obvious matter of design choice.
In the alternative, it is argued that, even were the exact timing of nuclease treatment to be found not to be a mere matter of design choice (which it is), merely treating the formulation of Oxford directly after the 0.2μm filter-sterilization step would be a matter of routine optimization to a person having ordinary skill in the art.
Oxford suggests to use multiple nuclease treatment steps in the method (Oxford, [0037]-[0040]). Thus, a person having ordinary skill in the art would have known from the teachings of Oxford that multiple nuclease treatment steps are suggested to be used.
Ausubel teaches a manufacturing process for the production of clinical-grade lentivirus which includes a step of ultrafiltration after a Benzonase® treatment step (Ausubel, Figure 8). According to Ausubel, ultrafiltration is sufficient to remove Benzonase® and produce clinical grade lentiviral vector formulations without the use of a sterile filter (Ausubel, page 7, fourth and fifth paragraphs). Thus, a person having ordinary skill in the art would have understood from the teachings of Ausubel that the same principal of using ultrafiltration to remove residual nucleic acids and Benzonase® enzyme applies in a lentiviral particle production context.
In teaching multiple nuclease treatment steps, Oxford exemplifies a method of producing lentiviral formulations wherein concentration is the last step in the method and suggests to use multiple nuclease treatment steps. To get to the method claimed in instant claim 1 a person having ordinary skill in the art need only decide to perform a nuclease treatment step just after the 0.2μm filter-sterilization step “(v)” as opposed to at step “(iv)” directly before step (v). This would have been a matter of routine optimization encompassing small changes in form to the method to a person having ordinary skill in the art. Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). Similarly to the case in In re Williams, the nuclease treatment occurring after step (v) in Oxford would have done “the same thing as the original invention” of Oxford “by substantially the same means”.
Therefore, claim 1 would have also been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention in view of Oxford and Ausubel as being a matter of routine optimization because the range of points at which nuclease is suggested to be added by Oxford is so close to the timing required by claim 1 and the modifications made to Oxford to arrive at the invention of claim 1 would have had nuclease doing the same thing in substantially the same way as in the instant invention and the results of doing so would have been predictable insofar as the nuclease would degrade residual nucleic acids and the method of Oxford would produce substantially the same final product.
Regarding instant claim 2 the method of Oxford comprises a clarification of supernatant step before a nuclease treatment step (Oxford, [0022]-[0023]).
Regarding instant claim 3, Oxford suggests multiple nuclease treatment steps within the method and Appel and Ausubel teach that nuclease treatment can occur at any point in the method because the final ultrafiltration will remove residual nucleases.
Regarding instant claim 4, the Benzonase® of Oxford possesses endonuclease activity (See Millipore Q&A).
Regarding instant claim 6, Benzonase® is a modified nuclease from Serratia marcescens (See Serratia nuclease Wikipedia).
Regarding instant claim 7, the first nuclease treatment in the method of Oxford precedes an ultrafiltration step (Oxford, Figure 1).
Regarding instant claim 8, the ultrafiltration of Oxford is tangential flow filtration (Oxford, [0029]).
Regarding instant claim 9, the tangential flow filtration of Oxford is through hollow fiber ultrafiltration (Oxford, [0029], 0201]).
Regarding instant claim 10, Oxford hypothesizes that lower vector concentration can lead to better recovery from sterile filtration, Oxford teaches that it is in fact the case that lower vector concentration prior to sterile filtration improves recovery, then Oxford explicitly teaches to dilute prior to sterile filtration (Oxford, [0245]).
Regarding instant claim 11, Oxford teaches to exchange the buffer with a formulation buffer prior to filter sterilization (Oxford, [0046]-[0049]). Between this teaching and the teaching to dilute the sample prior to filter sterilization supra, Oxford consequently teaches to dilute the vector preparation in formulation buffer prior to filter sterilization.
Regarding instant claim 12, the first ultrafiltration step of Oxford is taught as an ultrafiltration/diafiltration buffer exchange step into formulation buffer (Oxford, [0036], [0041]-[0048]).
Regarding instant claims 13 and 14, Oxford suggests multiple nuclease treatment steps. Therefore, the nuclease treatment step of Oxford which would follow the step of sterile filtration as was rendered obvious above in view of Appel and Ausubel in the alternative, would in some obvious embodiments be a second nuclease treatment step. In these embodiments, the nuclease treatment would be the penultimate step because concentration is the final step in the process of Oxford and Appel teaches that concentration by ultrafiltration removes residual nucleases.
Regarding instant claim 15, the Benzonase® of Oxford possesses endonuclease activity as evidenced by Millipore Q&A.
Regarding instant claim 17, the Benzonase® of Oxford is a modified nuclease from Serratia marcescens (See Serratia nuclease Wikipedia).
Regarding instant claim 27, the claimed methods steps are all encompassed in dependent claims 2-4, 6-15, and 17 rendered obvious directly above. For clarity of the record, Oxford teaches culturing cells that produce the lentiviral vector (Oxford, [0187]), harvesting the supernatant from the culture (Oxford, [0191]), clarifying the supernatant (Oxford, [0191]), treating the clarified supernatant with a nuclease (Oxford, Figure 1), concentrating the nuclease-treated clarified supernatant via ultrafiltration/diafiltration into a formulation buffer (Oxford, [0036], [0041]-[0048]), purifying the lentiviral vector in the formulation buffer (Oxford, [0201], [0203]), filter sterilizing the lentiviral vector preparation (Oxford, Figure 1), and concentrating the lentiviral vector preparation as the final step (Oxford, Figure 1). Notably, the purification via chromatography can occur after diafiltration according to the method of Oxford (Oxford, [0203]). In addition and as set forth above, it would have been, in the alternative, either an obvious matter of design choice or a matter of routine optimization to have had a second nuclease treatment step prior to the final concentration step.
Regarding instant claims 28-29, 35, and 37, Oxford discloses a molecular weight cutoff for the tangential flow filtration of 100 to 1000 kDa as appropriate for retroviral vectors (Oxford, [0201]).
Regarding instant claims 33, and 41-42, the ultrafiltration of Oxford is tangential flow filtration (Oxford, [0029]), and the tangential flow filtration of Oxford is through hollow fiber ultrafiltration (Oxford, [0029], 0201]).
Regarding instant claim 36, the Benzonase® of Oxford is a modified nuclease from Serratia marcescens (See Serratia nuclease Wikipedia).
Regarding instant claim 38, Oxford teaches that the purification by chromatography can be via size exclusion chromatography (Oxford, [0034]).
Response to Arguments
Applicant argues against the prima facie obviousness of the pending claims by arguing (1) Oxford teaches away from the presently claimed method, (2) filter-sterilization does not encompass the ultrafiltration disclosed in Ausubel, (3) Appel is silent with respect to lentiviral vectors and filter sterilization and used a 300kDa membrane and 5 diavolumes, and (4) the particular dilutions claimed are 184 times lower than the concentrations suggested by Oxford.
(1) Applicant argues “paragraph [0040] of Oxford cited by the Examiner clearly indicates that it is preferable to carry out any nuclease treatment steps before the filter-sterilization of step (v), which actually teaches away from the presently claimed method,” (Remarks, page 11). This argument has been fully considered but has not been found persuasive because disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). “A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use.” In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994). Furthermore, “[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). Oxford teaches to include multiple nuclease treatment steps generally. The fact that Oxford teaches preferable embodiments wherein the treatment occurs before or at step “(iv)” does not criticize, discredit, or otherwise discourage the addition of nuclease elsewhere in the method. Accordingly, the argument has been fully considered but has not been found persuasive.
(2) Applicant argues “As currently amended, the filter-sterilization step of the present claims does not encompass the ultrafiltration disclosed in Ausubel,” (Remarks, page 11). This argument has been fully considered but has not been found persuasive because the instant rejection has been modified as necessitated by Applicant’s amendment to not rely on the broadest reasonable interpretation of “filter-sterilization”. Since the pending claims now plainly require a 0.22μm filter, the rejection has been modified to rely on the broader teaching of Oxford in view of Ausubel’s teaching of ultrafiltration as sufficient to remove residual enzyme and nucleic acids in a lentiviral particle production context. Thus, the rejection no longer relies on the interpretation that this argument is rebutting and the argument has not been found persuasive. In response to applicant's other arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The fact that ultrafiltration is not the final step in the process of Ausubel does not cut against the obviousness of the instant invention here because Oxford teaches concentration as the final step in the process and Ausubel is relied upon for its teaching of ultrafiltration following nuclease treatment as sufficient to remove residual enzyme and nucleic acids in a lentiviral particle production context. Thus, the arguments against Ausubel alone are not found persuasive because the rejection was based upon a combination of Oxford and Ausubel.
(3) Applicant argues “Regarding Appel, the entire disclosure is silent with respect to lentiviral vectors and Appel is instead focused on the production of viral vaccines,” and “Appel states that a 300 kDa Biomax membrane was used and that 5 diavolumes were needed to achieve 99.5% clearance, and 8 diavolumes achieved 99.5% clearance. Residual Benzonase® was still observed in the retentate when only 1 or 3 diavolumes was used (see figure from bottom of center column of Appel, reproduced below). Therefore, not all conditions tested by Appel produced viral products with purity suitable for clinical use,” (remarks, page 13). In addition, Appel argues “Appel does not mention filter-sterilization and at what point in the process filter- sterilization should be performed relative to nuclease treatment,” (remarks, page 14). These arguments have been fully considered but have not been found persuasive because the rejection is based upon a combination of Oxford and Appel/Ausubel and is not based on any of these references in a vacuum. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Here, Oxford teaches to use a cutoff of 100 to 1000 kDa for the tangential flow filtration and Oxford teaches a filter-sterilization step. Appel is relied upon for the teaching of ultrafiltration as sufficient in itself for the removal of residual enzyme and nucleic acids. The fact that Appel teaches a 300kDa cutoff is irrelevant in this context because the amended claims apply a more stringent (500 to 1000 kDa cutoff) and Appel teaches that the less stringent 300kDa is sufficient. In addition, a person having ordinary skill in the art need not be confident that the 300kDa tangential flow step of Appel for vaccines would be appropriate to provide clinical-grade lentiviral vector as argued by Applicant for a prima facie case of obviousness to be established here. To get to the invention instantly claimed from the method of Oxford, all that a person of ordinary skill in the art would have needed was a teaching that the ultrafiltration step of Oxford would suffice to remove residual nucleic acids and enzyme from the viral preparation and a reasonable expectation of success in doing so because Oxford already taught ultrafiltration as the final step. A person having ordinary skill in the art, viewing Appel, would have understood that the ultrafiltration step of Oxford would suffice to remove residual nucleic acids and enzyme from the viral preparation of Oxford and they would have had a reasonable expectation of success in including a nuclease treatment after filter-sterilization and before ultrafiltration in the method of Oxford because Oxford suggests to use multiple nuclease treatment steps and Appel teaches that ultrafiltration is sufficient to remove nucleic acids and residual enzyme from the final preparation of virus. Thus, this argument has been fully considered but has not been found persuasive.
Applicant has also provided the Perry reference to argue that filter-sterilization is typically the final step in the process for lentiviral vectors (Remarks, page 15). This argument is not found persuasive because the Examiner has relied on Oxford which does teach a method where sterile-filtration is not the final step in the process.
(4) Applicant argues, “Even if the typical 100-1000 fold relationship between physical titer and infectious titer from Cell Biolabs FAQ did directly apply to this case (which it may not for the reasons described by Perry), the analogous physical titer for this suboptimal concentration would correlate to 4.84 x 108 to 4.84 x 109 copies per mL, which is significantly lower than the 4.6 x 1011 copies per mL maximum concentration suggested by Oxford. Along the same lines, instant claims 30 and 39 would cover an analogous physical titer of about 1.5 x 108 to 2.5 x 109 copies per mL, which at the highest claimed concentration is 184 times less than the concentration suggested by Oxford. Applicant respectfully submits that claims 30-31 and 39-40 provide concentrations of functional titers for filter-sterilization which provide improvements in yield for the preparation of lentiviral formulations,” (Remarks, page 19), and “As shown in Figure 3 of the instant application (reproduced below), a concentration of 4.84 x 106 infectious titer units per mL during sterile filtration provided a significantly lower yield than lower concentrations (over 60% less than the highest yield for 1.98 x 106 infectious titer units per mL sample),” (Remarks, page 18). This argument has been fully considered and has been found to be persuasive.
Oxford hypothesizes that lower vector concentration can lead to better recovery from sterile filtration, Oxford teaches that it is in fact the case that lower vector concentration prior to sterile filtration improves recovery, then Oxford explicitly teaches to dilute prior to sterile filtration (Oxford, [0245]). Oxford teaches high rates of recovery when vector concentrations were diluted to less than or equal to 4.6x1011 copies per ml (Oxford, [0246]). A person having ordinary skill in the art understands that a retroviral preparation typically has less infectious units per mL compared to overall copies of virus per mL (typically 100-1000 fold lower) as evidenced by Cell Biolabs FAQ (Cell Biolabs FAQ, whole document). Applicant has, in effect, argued that the concentrations claimed provide superior or unexpected properties over the concentrations taught by Oxford by arguing that even going from a concentration of 1.98 x 106 infectious titer units per mL to a concentration of 4.84 x 106 infectious titer units per mL reduces titer by 60%. Although, Oxford teaches to dilute the viral preparations before sterile filtration, it does not teach to dilute down to a concentration of about 1.5 x 106 to about 2.5 x 106 infectious titer units per mL and a person having ordinary skill in the art would not have reasonably expected such a drastic increase in viral titers from reducing the concentration of Oxford down to the level claimed. Accordingly, this argument has been fully considered and has been found persuasive. The rejection has been withdrawn with regard to pending claims 30-31, and 39-40.
New Objections Necessitated by Applicant’s Amendments/Arguments
Claims 30-31, and 39-40 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claim is allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRENDAN THOMAS TINSLEY whose telephone number is (703)756-5906. The examiner can normally be reached Mon-Fri 8:00-5:00.
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/BRENDAN THOMAS TINSLEY/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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