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 .
Response to Amendment
The Amendment filed 11/14/2025 in which claims 1, 2, 9-11, 23 were amended, claim 15 was canceled, has been entered. Claims 7-8, 14, 16, and 21 were previously cancelled.
Claims 1-6, 9-13, 17-20, 22, 23 are currently under examination on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) was submitted on 05/30/2025 and 07/01/2025, filed after the mailing date of the Non-final rejection on 05/16/2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 103
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.
(Previous rejection, withdrawn as to claims 1-6, 11-13, 15, 18-20 and 22-23) Claims 1-6, 11-13, 15, 18-20 and 22-23 were rejected under 35 U.S.C. 103 as being unpatentable over Lesch, et al. as evidenced by EXCELL in view of Vassilaki et al.; prior art of record, as evidenced by Baker “Understanding Dissolved Oxygen in Cell Culture” Published on 09/2014. See PTO-892: Notice of References Cited.
See claims 1-6, 11-13, 15, 18-20 and 22-23 as submitted on 11/14/2025.
The previous rejections of claim 15 is moot in view of Applicant’s cancelation of this claim.
Applicant’s amendment to the instant claims filed on 11/14/2025 has overcome previous rejection to claims 1-6, 11-13, 18-20 and 22-23.
(Previous rejection, withdrawn as to claims 9-10, 17) Claims 9-10 and 17 were rejected under 35 U.S.C. 103 as being unpatentable over Lesch in view of Vassilaki as applied to claims 1-6, 11-13, 15, 18-20 and 22-23 above, and further in view of Lim. Prior art or record.
See claims 9-10 and 17 as submitted on 11/14/2025.
Applicant’s amendment to the instant claims filed on 11/14/2025 has overcome previous rejection to claims 9-10, 17.
(New rejection, necessitated by amendment as to claims 1-6, 11-13, 18-20 and 22-23) Claims 1-6, 11-13, 18-20 and 22-23 are rejected under 35 U.S.C. 103 as being unpatentable over Lesch, et al. as evidenced by EXCELL in view of Vassilaki et al., as evidenced by Baker (prior art of record), further in view of Gallo-Ramirez et al. Bioreactor Concepts for Cell Culture-Based Viral Vaccine Production. Expert Review of Vaccines 2015, 14 (9), 1181– 1195. See PTO-892: Notice of References Cited.
See claims 1-6, 11-13, 18-20 and 22-23 as submitted on 11/14/2025.
Regarding claims 1, 11, and 23, it is noted that the amendment filed on 11/14/2025 introduced one limitation to these claims and their dependents. This limitation recites “Vero host cells”.
Lesch teaches HEK293 cells and Vassilaki teaches Huh7 cells. Neither Lesch nor Vassilaki teach the use of Vero host cell.
However, Gallo-Ramirez et al. teach Vero cells are widely used for optimal viral gene expression with signals for synthesis and culture-based viral vaccine production (Abstract). Gallo-Ramirez et al. further teaches human and animal cells such as Vero cells, HEK293 cells, etc. are commonly used for virus production and these cells functional equivalents for virus production (pages 2, 3). Further cells such as HEK293 and Vero cells have been adapted to grow in serum-free media thereby offering a cost advantage for large scale virus production (page 3). The teachings of Gallo-Ramirez et al. establish human and higher animal cell lines as functional equivalents for virus production (pages 1-5). See MPEP 2144.06: Substituting Equivalents Known For The Same Purpose.
It would have been prima facie obvious to a person of ordinary skill in the art, at the time of filing, to have employed Vero host cells as taught by Gallo-Ramirez et al. in the method of virus production taught by Lesch and Vassilaki for the benefit of using a well-established higher animal cell expression system for viral production, which can be grown in serum-free media. See MPEP 2144.06. Substituting Equivalents Known For The Same Purpose.
One of ordinary skill in the art would have had a reasonable expectation of success for introducing Vero host cells as taught by Gallo-Ramirez et al. in the method of virus production taught by Lesch and Vassilaki given that the methods of virus particle production are known, successfully demonstrated, and commonly used as evidenced by the applied prior art.
With respect to all other limitations of claims 1-6, 11-13, 18-20 and 22-23, as previously indicated, Lesch and Vassilaki in combination teach all of those limitations as follows.
First, the methods taught by Lesch include each active step, of the claims and all claimed experimental conditions, including the parameters of the bioreactor (single-use, fixed-bed bioreactor of height of 2 cm) (relevant to claims 3-5), adenovirus (relevant to claim 12) and cell type (adherent) (relevant to claim 2), the virus is a adenoviral vector (relevant to claim 13), characterizing the virus (relevant to claim 18), and producing vaccines with the produced virus (relevant to claim 19) (Abstract; page 562, col. 1 ¶ 1, page 568, col. 2 ¶ 2). Lesch further teaches the bioreactor is optimized for adenovirus production in a small scale (700 mL volume, 0.8 m2 culture area; Table 3) and then scaled up into a large-scale bioreactor (72.5 L volume, 100 m2 culture area; Table 3; Pages 568-569, bridging paragraph) (relevant to claim 20). Additionally, Lesch teaches methods where cells are grown in EXCELL 293 medium, which is an animal protein free medium (see EXCELL, prior art of record), without serum supplementation (Page 561, col. 2, para. 2; Page 564, col. 1, para. 2) (relevant to claim 22). Lesch further teaches the following experimental conditions: initial dissolved oxygen (dO2) levels of approximately 100% (Fig. 2 at time point 0) prior to infection, constant dissolved oxygen (dO2) set point of 50% air saturation (page 562, col. 1 ¶ 1), constant pH set point at 7.2, and constant temperature of 37°C (page 562, col. 1 ¶ 1; page 561, col 2, ¶ 2, Fig. 5) (relevant to claim 1 (b)). It is noted that Fig. 2 in Lesch’s teaching shows dissolved oxygen levels as “DO Air Sat” where the “DO” is an abbreviation for ‘dissolved oxygen’ and refers to the levels of dissolved oxygen in a culturing system and not to atmospheric air (Fig. 2; page 562, col. 1 ¶ 1).
Therefore, the teachings of Lesch render prima facie obvious the limitations of claim 1 (b) and claims 2-5, 12, 13, 18-20, 22, 23 (b) as submitted on 11/14/2025.
Lesch does not explicitly teach decreasing the levels of dissolved oxygen (dO2) prior to infecting the host cells as encompassed by claim 1 (c).
However, Vassilaki teaches that low oxygen tension enhances Hepatitis C virus replication (Abstract; Fig. 2). Vassilaki specifically teaches that Huh7.5 cells preincubated at 3% O2 or 12% O2 (reduced from 20% O2) for 18 hours prior to infection (relevant to claim 11) with supernatant containing Hepatitis C virus exhibit elevated Hepatitis C virus replication (Figs. 1-3; Fig. S6; Page 2944, col. 1, para. 2). As previously noted, a decrease of the dO2 to 20-90% of initial oxygen level as recited in instant claim 1 indicates a dO2 level of 10-80%. As previously explained, Vassilaki teaches a reduction of oxygen levels to 3% O2 or 12% O2 for 18 hours prior to infection from an initial dO2 level of 20% O2 which represents a decrease of dO2 of 15-60% of initial oxygen level (relevant to claim 1 (c), 23 (c)). These ranges overlap with the claimed ranges of dO2 levels and hours prior to infection. Instant claim 1 recites “20-90% of initial oxygen level” which overlaps significantly with the ranges taught by Vassilaki. Furthermore, the claimed ranges recited in claims 6 and 23 of “20-50% of initial oxygen level” are in fact entirely encompassed by the ranges taught by Vassilaki. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Therefore, the claimed ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
Regarding the limitations of claim 1 (f) as submitted on 11/14/2025, which recite “harvesting the virus after step e), wherein the decreased dO2 level of step c) is maintained constant through steps d), e), and f).” Vassilaki further teaches cells preincubated at the higher dO2 level of 20% and later cultured at 3% dO2 until harvest (Fig. 2A). Accordingly, the limitations of claim 1 (f), claims 6 and 23 are prima facie obvious in view of the teachings of Vassilaki.
It would have been a matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal dO2 levels and hours of incubation prior to infection as well as post infection to achieve high titers of viral particles with a reasonable expectation of success. 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). See also MPEP § 2144.05.
Accordingly, amended claims 1-6, 11-13, 18-20 and 22-23 of the claimed invention as submitted on 11/14/2025 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date especially in the absence of evidence to the contrary.
(New rejection, necessitated by amendment as to claims 9-10, 17) Claims 9-10 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Lesch in view of Vassilaki and Gallo-Ramirez et al. as applied to claims 1-6, 11-13, 18-20 and 22-23 above, and further in view of Lim. Prior art or record.
See claims 9-10, 17 as submitted on 11/14/2025.
Regarding claims 1, 9-10, it is noted that the amendment filed on 11/14/2025 introduced one limitations to these claims and their dependents. This limitation recites “Vero host cells”.
As explained above, the limitation of Vero cells is already taught by Gallo-Ramirez et al.
With respect to all other limitations of claims 9-10, 17 the cited prior art teaches all of those limitations as follows. The teachings of Lesch and Vassilaki are described above. However, they do not teach a method wherein the host cells are infected with virus at an MOIM of about 0.1 to 0.05, or 0.05. Nor do they teach a method where the virus titer is determined by plaque assay.
However, Lim teaches methods of producing VSV and that VSV titer was significantly increased (130 fold) when grown in spinner cultures at 10% oxygen, as compared to spinner cultures at 23% oxygen (Abstract; Table 1). Lim further teaches that virus titer was determined by standard plaque assay (Page 267, ¶ 2). Additionally, Lim teaches virus suspension at 0.1 MOI was added to the bioreactors to produce virus (Page 267, ¶ 1). The MOI recited by instant claims of about 0.1 - 0.05, or 0.05 is considered to be one determined by routine optimization according to one of skill in the art in view of the teachings of Lim.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to have applies the teachings of Lim to a method for producing virus as taught by Lesch in view of Vassilaki and Gallo-Ramirez et al. for the benefit of maximizing the virus production by using the optimal MOI and to precisely measure virus titers.
One of ordinary skill in the art would have had reasonable expectation of success in implementing an optimal MOI and subsequent plaque assay given that the methods of virus inoculation and virus titer measurement are well known, successfully demonstrated, and commonly used as evidenced by the applied prior art.
Accordingly, claims 9-10 and 17 would have been prima facie obvious to one of ordinary skill in the art at before the effective filing date especially in the absence of evidence to the contrary.
Double Patenting
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
(Previous rejection, withdrawn as to claims 1-3, 6, 9-13, 15 and 17-19) Claims 1-3, 6, 9-13, 15, and 17-19 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6-11, 16-19, and 21-23 of U.S. Patent No. 11827907, in view of Lesch, prior art of record.
See claims 1-3, 6, 9-13, 15, and 17-19 as submitted 11/14/2025.
The previous rejections of claim 15 is moot in view of Applicant’s cancelation of this claim.
Applicant’s filing of a terminal disclaimer submitted on 11/14/2025 is acknowledged. The previous rejection provisional rejection on the ground of nonstatutory double patenting over U.S. Patent No. 11827907 is herein withdrawn.
(Previous rejection, withdrawn as to claims 1-2, 6, 11-13, 15 and 23) Claims 1-2, 6, 11-13, 15 and 23 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 8-10, and 23-25 of copending Application No. 17/561,389 in view of Lesch and Vassilaki, prior art of record.
See claims 1-2, 6, 11-13, and 23 as submitted 11/14/2025.
The previous rejections of claim 15 is moot in view of Applicant’s cancelation of this claim.
Applicant’s filing of a terminal disclaimer submitted on 11/14/2025 is acknowledged. The previous rejection provisional rejection on the ground of nonstatutory double patenting over copending Application No. 17/561,389 is herein withdrawn.
(Previous rejection, withdrawn as to claims 1-2, 9-13, 15, and 23) Claims 1-2, 9-13, and 23 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 86-88, 90 and 93-94, 96-97 of copending Application No. 18/379,644 in view of Vassilaki, et al. Prior art of record.
See claims 1-2, 9-13, 15 and 23 as submitted 11/14/2025.
The previous rejections of claim 15 is moot in view of Applicant’s cancelation of this claim.
Applicant’s filing of a terminal disclaimer submitted on 11/14/2025 is acknowledged. The previous rejection provisional rejection on the ground of nonstatutory double patenting over copending Application No. 18/379,644 is herein withdrawn.
Response to Argument
Applicant's arguments filed on 11/14/2025 have been fully considered but they are not persuasive.
Applicant contends on page 7 of the Remarks submitted on 11/14/2025:
Here, the combination of Lesch et al. and Vassilaki et al. does not establish a prima facie case of obviousness. In particular, Applicant respectfully submits that the Examiner has not successfully demonstrated that there is any motivation to combine Lesch et al. and Vassilaki et al., and assuming arguendo that they are combined, that the skilled artisan has a reasonable expectation of successfully producing the claim 1 method.
In response:
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the cited prior art provides clear teachings, suggestions and motivation to arrive at the claimed method. As explained above in detail, Vassilaki teaches the clear benefit of enhanced virus replication upon low oxygen tension prior to infection. Thus, one of ordinary skill in the art would have been motivated and had a reasonable expectation of success to decrease the levels of dissolved oxygen prior to infecting the host cells to achieve enhanced virus production as taught by Vassilaki.
Applicant contends on page 7 of the Remarks submitted on 11/14/2025:
Lesch et al. and Vassilaki et al. clearly indicate that their respective test conditions are specific to the cell lines of those references (HEK293 cells in Lesch et al. and Huh7 cells in Vassilaki et al. Indeed, Lesch et al. teaches that "the adherent HEK293 cell line was crucial because the productivity of this specific vector in adherent mode was much higher than in suspension . .. ." Lesch et al. at 568 (emphasis added). As noted above, HEK293 must be grown under the correct conditions to adhere efficiently. Id. at 561. Vassilaki et al. found that its conditions of lowering 02 from atmospheric (20% 02) down to hypoxic (3% 02) enhanced HCV replication in Huh7 cells. Thus, these references show virus production under specific conditions for specific cell lines.
In response:
Applicant’s argument regarding the specific cell lines is not persuasive because as taught by Gallo-Ramirez et al. it is well known in the art that numerous cell lines can be successfully used in methods of virus production. In the instant case, the art clearly recognizes that Vero cells are functional equivalents of the cell lines taught by the cited prior art. See MPEP 2144.06. Substituting Equivalents Known For The Same Purpose: In order to rely on equivalence as a rationale supporting an obviousness rejection, the equivalency must be recognized in the prior art, and cannot be based on applicant’s disclosure or the mere fact that the components at issue are functional or mechanical equivalents. In re Ruff, 256 F.2d 590, 118 USPQ 340 (CCPA 1958).
Applicant contends on page 9 of the Remarks submitted on 11/14/2025:
Lim et al. does not, however, teach or suggest that use of the specific cell culture conditions for the specific cells lines of Lesch et al. and Vassilaki et al. would provide the skilled artisan with a reasonable expectation of successfully replicating the Lesch et al. and Vassilaki et al. results with Vero cells. Thus, the combination of Lesch et al., Vassilaki et al., Lim et al. does not teach or suggest a method of producing virus in a bioreactor comprising providing Vero host cells in the bioreactor; growing the Vero host cells at a constant initial d02 level of 100%, at a constant pH and a constant temperature; decreasing the d02 level to 20-90% of the initial d02 level and continuing to grow the Vero host cells for 2 to 24 hours prior to infecting the Vero host cells at the decreased d02 level; infecting the Vero host cells with at least one virus or virus particle; incubating the Vero host cells infected with the virus or virus particle to propagate the virus; and harvesting the virus, wherein the decreased d02 level is maintained constant through the final three steps.
In response:
Applicant's arguments against the references individually are not persuasive because 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). As explained above and previously, Lim was cited for teaching a method wherein the host cells are infected with virus at an MOI of about 0.1 to 0.05, or 0.05. and where the virus titer is determined by plaque assay. Gallo-Ramirez et al. was cited for teaching numerous cell lines including Vero cells for virus production.
Conclusion
No claims are 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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARLENE V BUCKMASTER whose telephone number is (703)756-5371. The examiner can normally be reached M-R 8:00 AM - 5:00 PM.
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/MARLENE V BUCKMASTER/Examiner, Art Unit 1672
/NICOLE KINSEY WHITE/Primary Examiner, Art Unit 1672