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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 June 22, 2026 has been entered.
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on June 22, 2026. Claims 9-12 and 18-20 are pending and currently examined.
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.
(New Rejection-necessitated by amendment) Claims 9-12 are rejected under 35 U.S.C. 103 as being unpatentable over Andre et al. (WO 2010/052214 A2, published on May 14, 2010) as evidenced by Herrera-Rodriguez et al. (Vaccine. 2019 Mar 14;37(12):1630-1637).
The amended claim 9 is directed to a method of producing an inactivated whole virus influenza vaccine composition, the method comprising:
A) providing a composition comprising influenza virus collected from a host;
B) treating the composition comprising influenza virus collected from a host of A) with P-propiolactone at a final concentration of β-propiolactone of from 0.0125% (v/v) to 0.1% (v/v) and incubating at a temperature of from 2°C to 8°C for at least 18 hours, to provide a composition comprising 3-propiolactone treated influenza virus; and
C) treating the composition comprising treated influenza virus of B) with formaldehyde by adding formalin at a final concentration of formalin of 0.02% (v/v) and incubating at a temperature of 4°C to 8°C for from 3 to 14 days.
Andre et al. teaches an invention that relates to a cell culture-based method of producing influenza vaccine, which provides a method for reducing the amount and/or the size of contaminating residual nucleic acids from host cells through the implementation of at least two distinct degradation steps performed by an endonuclease, such as Benzonase TM, and/or by a DNA alkylating agent, such as beta-propiolactone (BPL), or by a combination (See page 1, lines 10-18; page 24, lines 6-11). Andre et al. teaches the step of providing a composition comprising a virus, or a viral antigen by the following:
a) providing a population of cells cultured in a cell culture medium,
(b) inoculating the population of cells with a virus,
(c) culturing the population of cells so as to allow the virus to replicate,
(d) collecting the produced virus thereby providing a viral harvest, and
(e) isolating the virus,
Here it provides a composition comprising a virus obtainable from the host cells by the method of the invention (See page 3, lines 1-20). Therefore, Andre et al. teaches the claim 9 A).
Andre et al. further teaches that BPL inactivation can be used at a concentration ranging from 0.01 % to 0.1 %, and the incubation time may vary. In particular, BPL is suitably incubated for an overnight period. BPL is active in a wide range of temperatures. In one embodiment of the present invention, BPL is incubated at a temperature ranging from 2 to 8°C. In a distinct embodiment, BPL is incubated at room temperature (See page 18, lines 30-37). Here Andre et al. teaches the claimed concentration range between from 0.0125% (v/v) to 0.1% (v/v), the temperature ranges from 2°C to 8°C and the incubation time range at least 18 hours (overnight).
Although Andre et al. does not disclose the unit of the BPL concentration here, Andre et al. teaches using the unit (V/V) in their invention such as immunogenic composition in an amount of 0.5% to 10% (v/v) (See e.g., page 22, paragraph 1). Also, it is a common knowledge in the art that the BPL (beta-propiolactone) concentration is typically measured and expressed as a volume per volume (v/v) ratio. This can be evidenced by Herrera-Rodriguez’s study. Herrera-Rodriguez teaches using the BPL to inactive influenza virus at a final concentration of 0.1% V/V and inactivation was done by overnight incubation at 4OC (See page 1631, right column, paragraph 3). Therefore, Andre et al. teaches the claim 9 B).
Andre et al. teaches that in a specific embodiment, the method according to the invention further comprises at least one BPL treatment step and at least one formaldehyde treatment step. Formaldehyde and BPL may be used sequentially, in any order, for instance, formaldehyde is used after the BPL (See page 21, lines 4-17). Here the description of Andre teaches a part of the claim 9 C) at treating the virus first with BPL and then followed by the treating with formaldehyde. As for the incubation time and temperature for the formaldehyde treatment, Andre et al. teaches that the formaldehyde was added to detergent-inactivated pools of viruses to further inactivate the virus. Formaldehyde is added at a ratio of 50 μg for 250 μg total proteins. A 0.2 μm sterilizing grade filtration was performed immediately after formaldehyde addition. Incubation lasts 72 hours at room temperature in sterile conditions (See page 29, paragraph 2). Although Andre et al. does not disclose the concentration (v/v) as claimed, it is well within the purview of one of ordinary skill in the art to express the concentration as different units. For an evidence, Herrera-Rodriguez et al. teaches two protocols for influenza inactivation using formaldehyde: 37% formaldehyde was used at a final concentration of 0.01% v/v and incubation was for 48 h (FA-2). Another protocol is involved the use of formaldehyde at a final concentration of 0.01% v/v but incubation was done for 96 h (FA-4). All incubations were performed at 4 °C under constant stirring (See page 1631, left column, paragraph 2). It would be obvious to express the concentration as a ration (Andre et al.) or as (v/v) (Herrera-Rodriguez et al.). Therefore, the claimed formalin condition would have been obvious unless there is evidence showing that the claimed percentage produced unexpected results. Accordingly, the claim 9 C) would have been obvious based on the teachings of Andre as evidenced by Herrera-Rodriguez.
In addition, according to section 2144.05 of the MPEP, 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 Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”). Based on the teachings of Andre et al., one of ordinary skills would be able identify an optimal formalin/BPL concentration, incubation time and temperature as claimed through routine experimentation. Therefore, the claimed formalin/formaldehyde concentration, time and temperature would have been obvious unless there is evidence showing that they produce unexpected results.
Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding claims 10-12, Andre et al. teaches that BPL was added at a final concentration of 0.05% and incubated overnight at a temperature ranging from 2°C to 8°C (See page 31, lines 1-10), where the overnight incubation can be close to 24 hours.
(New rejection) Claims 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Andre et al. (WO 2010/052214 A2, published on May 14, 2010) as evidenced by Herrera-Rodriguez et al. (Vaccine. 2019 Mar 14;37(12):1630-1637) as applied to claims 9-12 above and in view of Pawar et al. (J Virol Methods. 2015 Sep 15;222:28-33).
Regarding claims 18-19, they require the formaldehyde treatment condition is at a temperature of from 4°C to 8°C for from 7 to 14 days.
Although Andre does not explicitly teach the incubation time and temperature as claimed for formaldehyde inactivation, as an evidence reference, Herrera-Rodriguez teaches a protocol comprises a formaldehyde inactivation condition at 4°C for 96 h (See page 1631, right column, paragraph 2). It would be obvious for one of ordinary skill in the art to select a known incubation temperature such as the claimed 4°C for influenza formaldehyde inactivation, and the result would be predictable by combining the teachings from Andre and Herrera-Rodriguez. Here the description teaches the temperature requirement of Claim 18 and the claim 19.
As for the requirement for incubation for 7-14 days in claim 18, Herrera-Rodriguez teaches use three standard inactivation protocols for influenza virus inactivation. In the second protocol, 37% formaldehyde was used at a final concentration of 0.01% v/v and incubation was for 48 h (FA-2). The third protocol also involved the use of formaldehyde at a final concentration of 0.01% v/v but incubation was done for 96 h (FA-4) (See page 1631, right column, paragraph 2). At the same time, Andre teaches that the formaldehyde was added to detergent-inactivated pool of viruses to further inactivate the virus. Formaldehyde is added at a ratio of 50 μg for 250 μg total proteins. A 0.2 μm sterilizing grade filtration was performed immediately after formaldehyde addition. Incubation lasts 72 hours at room temperature in sterile conditions (See page 29, lines 11-15).
Based on the teachings above, although Andre in view of Herrera-Rodriguez does not teach the exact incubation time, it indicates that the incubation time of formaldehyde inactivating influenza is related to formaldehyde concentration, temperature, and initial viral load/density, and it can be adjusted to the claimed incubation time through routine experimental optimization.
Nevertheless, Pawar teaches that it has been shown that different subtypes of influenza viruses require different physical and chemical condition for inactivation of infectivity (See page 29, left column, paragraph 3) and the influenza virus can be inactivated by formaldehyde at the final concentrations of 0.02%, 0.04% and 0.1% for three different incubation time points (16 h at 37◦C, 48 h at 37◦C, 1 week at 4◦C) (See page 29, right column, paragraph 2; Table 1 and below), where the 1 week incubation teaches the claim 18 for the incubation limitation at 7 to 14 days.
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It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Andre, Herrera-Rodriguez and Pawar to arrive at an invention as claimed. One of skill in the art would have been motivated to do so to introduce the known incubation time for 7 days of Pawar into Andre’s invention to inactive the influenza. There would be a reasonable expectation of success to develop an incubation time for formaldehyde inactivation as claimed.
(New rejection) Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Andre et al. (WO 2010/052214 A2, published on May 14, 2010) as evidenced by Herrera-Rodriguez et al. (Vaccine. 2019 Mar 14;37(12):1630-1637) and in view of Pawar et al. (J Virol Methods. 2015 Sep 15;222:28-33) as applied to the claims 9-12 and 18-19 above, and further in view of Haredy et al. (Immunol. 2013 Jul;20(7):998-1007).
Claim 20 requires that the incubating is for 14 days.
Based on the description above, Andre as evidenced by Herrera-Rodriguez in view of Pawar teaches a different incubation time for formaldehyde inactivation. Although these incubation time does not teach the required time of claim 20 at 14 days, however, the teachings from Andre as evidenced by Herrera-Rodriguez in view of Pawar indicate that the incubation time for formaldehyde treating influenza can be varies based on formaldehyde concentration, temperature, influenza strains/subtypes, and initial viral load/density, and it can be adjusted through routine experimental optimization.
Based on the Table 1 (See below) of Pawar, the incubation days can be adjusted based on the different strain of influenza virus.
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This can be further in viewed by Haredy’s study. Haredy discloses that they produced a formalin-inactivated whole-virion vaccine from the MDCK cell-cultured A /duck/Hokkaido/Vac-3/2007 (H5N1) P22 virus (Se Abstract), and teaches an incubation time at 0.02% formalin for 28 days at 4°C (See page 1000, right column, paragraph 3). Although the 28 days incubation is longer that 14 days as claimed in claim 20, it further teaches that the incubation time for formaldehyde treating influenza can be optimized based on the different viral strain or subtype such as the highly pathogenic H5N1 of Haredy, chemical concentration, and temperature.
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Andre, Herrera-Rodriguez, Pawar and Haredy to arrive at an invention as claimed. One of skill in the art would have been motivated to do so to test for an optimal incubation time such as 14 days as claimed at a specific formaldehyde concentration to inactive a specific influenza subtype through routine experimentation unless there is evidence showing that they produce unexpected results. Since the formaldehyde incubation time of Andre as evidenced by Herrera-Rodriguez in view of Pawar and Haredy is form hours to 28 days that includes the claimed 14 days, there would be a reasonable expectation of success to develop such an incubation time for formaldehyde inactivation as claimed.
Responses to Applicant’s Remarks
Applicant’s arguments filed on June 22, 2026 has been received and fully considered.
Applicant’s argument on the rejections Under 35 U.S.C. § 103 is not found persuasive as follows:
1. Applicant argued a surprisingly result for a reduction in the innate immune activation capacity of an influenza vaccine antigen by formaldehyde based on the TLR activity in Table 1 and Table 2 (See Remarks, pages 5-6).
Applicant’s argument is not persuasive.
1). The argument points, “surprisingly that a reduction in the innate immune activation capacity of an influenza vaccine antigen by formaldehyde can be prevented by treating the influenza virus in advance with P-propiolactone…”, which showed in Table 1 and Table 2 (See Remarks, page 6), are not recited in the base claim 9. The base claim 9 only claims a method of producing an inactivated whole virus influenza vaccine composition, and does not recite a limitation of function for preventing “reduction in the innate immune activation capacity of an influenza vaccine antigen by formaldehyde”, and does not recite a limitation on enhancing or reducing a “Relative activity value” in a specific influenza strain as summarized in the Tables 1 & 2.
Also, Andre teaches a method to inactive influenza by using formaldehyde after the BPL (See page 21, lines 4-17). With the same steps of inactivation, they should produce a comparable result.
Accordingly, the argued surprising result is not persuasive.
2). The base claim 9 is directed to a method of producing an inactivated whole virus influenza vaccine composition, where the claimed “whole virus influenza” can be any influenza virus strain or subtypes. However, the alleged data in Table 1 and Table 2 are specific for the B/Phuket/3073/2013 strain and A/Kansas/ 14/2017 strain.
Therefore, the data in the Table 1 and 2 can not be considered as a surprising result.
3). Applicant argued that “the values identified in bold font are underlined in the specification as filed, because it was considered that a significant reduction of the TLR activation capacity was observed in the conditions indicated by underlined values in the table” (See Remarks, page 7).
The argument is not found persuasive because the specification does not provide data and evidence for demonstrating how much changes for the TLR activation capacity is “significant”.
2. Applicant argued that they amended the claim 9 to a final concentration at “formalin 0.02% (v/v) and incubating at a temperature of from 4°C to 8°C for from 3 to 14 days." (See Remarks, pages 4-5).
The argument is not found persuasive because the newly amended condition has been obvious based on the teachings of Andre as evidenced by Herrera-Rodriguez.
In addition, according to section 2144.05 of the MPEP, 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 Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”).
3. Applicant argued that “Yet the Office Action does not address either the required motivation or the required reasonable expectation of success that a person of ordinary skill in the art must have had in order to have considered the asserted combination of these references. Here, there is no reason to modify or combine the cited references, and so there cannot be any reasonable expectation of success in pursuing their asse1ted combination” (See Remarks, page 8).
Applicant’s argument is not found persuasive.
The reference of Herrera-Rodriguez is used as evidence for the office action on “Although Andre et al. does not disclose the concentration as (v/v) as claimed, it is well within the purview of one of ordinary skill in the art to express the concentration as different units”, and used for evidence that the incubation temperature and time can be adjusted through routine experimental optimization. Indeed, Herrera-Rodriguez indicates that the alterations caused by BPL or FA treatment were virus strain dependent. This data shows that the inactivation procedures should be tailored on the virus strain (See Abstract).
4. Applicant argued that applicant also submits that the amended claims define embodiments that the specification demonstrates are unexpectedly superior to prior art methods, including any methods that may have been suggested by the cited art. The amended claims are commensurate in scope with the unexpected results (See Remarks, page 10).
Applicant’s argument is not found persuasive.
Applicant’s attention is directed to MPEP 716.02(b)-(e) for how unexpected
results can be established. To evaluate if the claimed invention produces unexpected
results, one must consider if the results produced by the claimed invention are
commensurate in scope with the claims and how the results compare with the closest prior art. See MPEP Section 716.02(d) and (e).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RUIXUE WANG whose telephone number is (571)272-7960. The examiner can normally be reached Monday-Friday 8:00 am to 4:30 pm, EST.
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/RUIXUE WANG/ Examiner, Art Unit 1672
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