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 .
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Sept. 04, 2025. Claims 9-17 are pending and currently examined.
Claim Objections
(Previous objection-withdrawn) Claims 1-8 are objected to because of the following informalities:
The base claim 1 describes a method for producing an inactivated influenza vaccine “the method comprising: treating a virus solution comprising an influenza virus collected from a host with β-propiolactone in advance, in an inactivation treatment using formaldehyde”, which makes the treating steps confused.
This objection is withdrawn in view of the amendments filed on Sept. 04, 2025.
Claim Rejections - 35 USC § 112 (b)
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.
(Previous rejection-withdrawn) Claims 2-4 and 6-8 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point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.
This rejection is withdrawn in view of the amendments filed on Sept. 04, 2025.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(Previous objection-withdrawn) Claims 1 and 5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Andre et al. ( WO 2010/052214 A2, published on May 14, 2010).
This rejection is withdrawn in view of the amendments filed on Sept. 04, 2025.
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.
(Previous objection-withdrawn) Claims 2 and 7- 8 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 applied to claims 1 and 5 above and as evidenced by DUKE-Light Microscope Core facility.
This rejection is withdrawn in view of the amendments filed on Sept. 04, 2025.
(Previous objection-withdrawn) Claims 3 and 6 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 DUKE-Light Microscope Core facility as applied to claims 1-2, 5 and 7-8 above, and in view of Sanders et al. (Vaccine Analysis: Strategies, Principles, and Control. 2014 Nov 28:45–80).
This rejection is withdrawn in view of the amendments filed on Sept. 04, 2025.
(Previous objection-withdrawn) Claim 4 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 applied to claims 1 and 5 above.
This rejection is withdrawn in view of the amendments filed on Sept. 04, 2025.
(New Rejection-necessitated by amendment) Claims 9-17 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).
New 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 p3-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 from 0.005% (v/v) to 0.01% (v/v) and incubating at a temperature of from 2°C to 8°C for from 3 to 14 days or at a temperature of from 20°C to 30°C for up to 3 days to provide an inactivated whole virus influenza vaccine composition.
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). Here, 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). Here Andre et al. teaches a part of the claim 9 C) at the claimed temperature of from 20°C to 30°C for up to 3 days by stating “the 72 hours at room temperature”. As for the concentration of formaldehyde, Andre et al. teaches formaldehyde being added at a ratio of 50 μg for 250 μg total proteins. 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. 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. In addition, the conditions used by Herrera-Rodriguez also teach claims 13-17 in that the incubation temperature is 2°C to 8°C or 4°C for from 3 to 14 days (96h =4 days), and a final concentration of formalin of 0.01% (v/v).
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.
Responses to Applicant’s Remarks
Applicant’s arguments filed on Sep. 04, 2025 has been received and fully considered as follows:
1. The objection is withdrawn based on applicant’s amendment.
2. The rejections under 35 U.S.C. § 112 (b) are withdrawn based on Applicant’s amendment.
3. The rejection Under 35 U.S.C. § 102(a)(l) is withdrawn based on Applicant’s amendment. The argument regarding the 102 is moot.
4. The rejections Under 35 U.S.C. § 103 on claims 2-4 and 6-8 are withdrawn based on Applicant’s amendment. The argument regarding the 103 is moot. A new 103 rejection-necessitated by amendment is issued in the current action.
5. 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, bridging pages 7-8).
Applicant’s argument is not found persuasive.
1). The base claim 9 claims an influenza inactivation method with both BPL and formalin at a certain range of time, concentration and temperature. The tables 1 and 2 only list the TLR activity under the formalin treatment without the BPL’s condition, and does not provide evidence if the claimed condition of pre-treating with BPL can affect the surprising result.
2). The Tables 1 and 2 only listed the concentration of formalin at 0.01 v/v and 0.02 v/v. The applicant does not show evidence if all the range of the concentrations of formalin at 0.005% to 0.01 % can produce the alleged surprising result.
In addition, the instant specification discloses that FIG. 4 shows the influence of formaldehyde treatment on the BPL-treated inactivated whole-virus vaccine of the B/Phuket/3073/2013 strain (BNamagata lineage). In the reaction condition of 4° C., no clear reduction in the TLR activation capacity was observed in 3 to 14 reaction days at the formalin concentration of 0.01 % (FIG. 4(A)), and in the reaction condition of 25° C., a tendency of a reduction in the TLR activation capacity with an increase in the formalin concentration was observed regardless of the number of days of the reaction (FIG. 4(8)) (See [0075], instant specification), which indicates that the claimed formalin concentration of 0.01 % at 4° C does not produce a surprising reduction in the innate immune activation capacity as claimed.
3). The Tables 1 and 2 only listed the result of formalin at 4° C and 25° C, and at days 3, 7 and 14. The applicant does not show evidence if all the range of the incubation time and temperature that are from 2°C to 8°C for from 3 to 14 days or at a temperature of from 20°C to 30°C for up to 3 days as claimed can produce the same alleged surprising result.
4). It is a common knowledge in the art that the influenza virus inactivation conditions depend significantly on the specific strain type as well as the inactivating agent used. The instant specification also discloses that although inactivation treatment of viruses has conventionally been performed by a long-time reaction at a formalin concentration of 0.02% at 4 ° C., it is suggested that sensitivity to formaldehyde is high in some strains (See [0077]) that indicates the variation of the influenza inactivation condition. This also is reflected by the Tables 1 and 2 as argued. Therefore, the alleged surprising data argued and supported by Tables 1-2 cannot be considered as an unexpected result to a generic influenza virus as claimed in the amended base claim 9.
5). Applicant’s attention is also 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.
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 RUIXUE WANG whose telephone number is (571)272-7960. The examiner can normally be reached Monday-Friday 8:00 am-5:00 pm, EST.
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/RUIXUE WANG/Examiner, Art Unit 1672
/NICOLE KINSEY WHITE/ Primary Examiner, Art Unit 1672
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