DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-27 were previously pending.
Receipt is acknowledged of the Amendments to the claims submitted on 17 February, 2026. Claims 1-4, 6-9, 12-13, and 27 are amended. Claims 5, 16, and 18-26 are cancelled. Claims 28-40 are newly added.
Applicant's election with traverse of the invention of group I (claims 1-17) in the reply filed on 17 February, 2026 is acknowledged. The traversal is on the ground that claim 1 is not anticipated by Truran, the International Searching Authority did not find a lack of unity of invention, and the shared technical feature between the inventions should have required nuclease treatment after filter-sterilization (Remarks, at pages 7-8). This is not found persuasive because the Examiner did not allege that Truran anticipated previous claim 1. Previously presented claims which are now cancelled did not require any particular order to the filter-sterilization and nuclease treatment steps. Thus, the shared technical feature did not require any particular order and Truran disclosed such a shared technical feature precluding its designation as a special technical feature for the purpose of determining unity of invention. The quoted language provided by Applicant exemplifies this characterization. Instead of addressing the claims which did not require filter sterilization and nuclease treatment in any particular order, Applicant has opted to cancel them and argue as if they never existed. In addition, the Examiner is not bound by the findings of the International Searching Authority. Therefore, the arguments have been fully considered but have not been found persuasive.
The requirement is still deemed proper. Upon further consideration, the Restriction Requirement between the inventions of groups I and IV is withdrawn. Since all presently pending claims read on the inventions of groups I and IV, no claims are withdrawn from consideration. It is noted that Applicant failed to properly label claim 27 as withdrawn in the Response submitted on 17 February, 2026. This is no longer an issue as mentioned above but Applicant should be aware that, upon election, whether with or without traverse, Applicant should properly label pending claims as withdrawn when they do not read on the elected invention. See 37 C.F.R. 1.142.
Therefore, claims 1-4, 6-15, 17, and 27-40 are pending and under examination in the present Official Action.
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 statements (IDS) submitted on 09 February, 2023, 04 November, 2025, and 17 February, 2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The drawings are objected to because FIG. 1 is out of focus and illegible while FIGs. 2-3 are missing axis labels. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-4, 6-9, 12-13, and 28-29 are rejected 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.
Claim 2 is rejected for being indefinite because it is unclear where the step of clarification is intended to occur to fall within the scope of the claim. Claim 1 from which claim 2 depends recites “(a) treating a filter-sterilized lentiviral vector preparation”. Thus, sometime prior to step (a) in claim 1, a step of filter-sterilization must occur. Claim 2 recites “prior to step (a), a clarification of a supernatant comprising cell culture media and the lentiviral vector”. It is unclear whether the step of clarification recited in claim 2 is intended to occur before of after the filter-sterilization step. This lack of clarity is amplified by the fact that clarification of cell culture supernatant typically occurs before any downstream processing like filter sterilization. Accordingly, a person having ordinary skill in the art would not be apprised of the scope of the patent protection sought.
Claims 3-4, 6-9, 12, and 28-29 are further rejected for their dependency on a rejected base claim.
Claim 13 depends from claim 1 and recites “wherein step (a) is a second nuclease treatment step”. The invention encompassed by instant claims 1 and 13 only has a single nuclease treatment step. Consequently, it is unclear whether Applicant intends the scope of claim 13 to encompass multiple nuclease treatment steps wherein step (a) is the second one or whether Applicant instead intends the scope of claim 13 to encompass a single nuclease treatment step. Accordingly, a person having ordinary skill in the art would not be apprised of the scope of the patent protection sought by the invention of instant claim 13.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 1-4,6-15,17 and 27-40 are 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.
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 (Oxford, Figure 1).
Therefore, 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), the broadest reasonable interpretation of filter sterilizing as informed by the instant specification encompasses ultrafiltration as taught by Ausubel and that merely treating the formulation of Oxford directly after the first ultrafiltration purification stem as opposed to right at said step would be a matter of routine optimization to a person having ordinary skill in the art. This alternative argument is set forth directly below.
Oxford suggests to use multiple nuclease treatment steps in the method and suggests to do so within a range up to and including the step of purifying (Oxford, [0037]-[0040]). Oxford teaches that tangential flow filtration, a type of ultrafiltration, is widely used in the bioprocessing industry for cell harvesting, clarification, purification and concentration (Oxford, [0201]). 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 and that ultrafiltration as a technique is a form of purification.
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 Applicants, filter sterilization encompasses any filtration which provides vector for clinical use (See US2023/0304037, [0069]). Although this is a non-limiting example, it nonetheless is helpful in establishing the broadest reasonable interpretation of filter sterilization encompassed by instant claim 1. According to Ausubel, ultrafiltration is sufficient to produce clinical grade lentiviral vector formulations. Thus, ultrafiltration is a sterile filtration step within the broadest reasonable interpretation of claim 1 as informed by the instant specification.
In teaching multiple nuclease treatment steps in the method of Oxford within a range up to and including at the step of purifying wherein purifying encompasses ultrafiltration, Oxford exemplifies a method of producing lentiviral formulations wherein concentration is the last step in the method and suggests to use a nuclease treatment step within a range of time points ending with purification (as taught by Ausubel as encompassing ultrafiltration). 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 ultrafiltration purification step of Oxford as opposed to at said step. 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 purification (which encompasses filter sterilization under the BRI of claim 1) 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 teaches 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, 34-35, 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 30-31, and 39-40, 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). Thus, a person having ordinary skill in the art would understand Oxford’s teaching of diluting to less than 4.6x1011 copies per ml prior to filtration to encompass diluting to around 100 to 1000-fold less infectious units per mL. This encompasses the claimed level of dilution. To any extent it can be argued that it doesn’t, it is noted that generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.).
Regarding instant claims 32-33, 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]).
Conclusion
No claim is allowed.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MARIA G LEAVITT can be reached at 571-272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BRENDAN THOMAS TINSLEY/Examiner, Art Unit 1634
/MARIA MARVICH/Primary Examiner, Art Unit 1634
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