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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 Mar. 16, 2026.
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Mar. 16, 2026. Claims 1-5 and 7-17 are pending and currently examined.
Claim Objections
(Previous objection-withdrawn) The base claim 1 objected to because of the following informalities: the “an” in the phrase “wherein an inactivated virus is...” should be “the”.
This objection is withdrawn in view of the amendments filed on Mar. 16, 2026.
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.
(Previous rejection-withdrawn) Claims 1-18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and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This rejection is withdrawn in view of the amendments filed on Mar. 16, 2026.
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 1 and 4-5, 7-14 are rejected under 35 U.S.C. 103 as being unpatentable over Kon et al. (PLoS One. 2016 Mar 9;11(3): e0150700) as evidenced by Sarkar et al. (Biologicals. 2017 Jul; 48:10-23), Sirasitthichoke et la. (Biotechnol Bioeng. 2023 Jan;120(1):169-183), Sanders et al. (Strategies, Principles, and Control. 2014 Nov 28:45–80), Gillespie et al. (Biotechnol J. 2019 Feb;14(2): e1700718), Meer et al. (Vox SanguinisVolume 111, Issue 2 pp. 127-134, May 11, 2016), and Barbero et al. (WO2017109223A1, published on June 29, 2017).
The amended base claim 1 is directed to a method of producing an inactivated viral vaccine wherein an inactivated virus is an active pharmaceutical ingredient, the method comprising:
(a)contacting a liquid composition comprising a live virus with a chemical viral inactivating agent in a container to form a mixture in a batch process;
(b) mixing the mixture by subjecting the container to agitation for a period of 1-60 minutes after the contacting of step (a);
(c) incubating the mixture for a period of time from 1 to 20 days to inactivate the virus, wherein no further agitation is performed after the initial mixing of step (b).
Kon et al. studies the Influenza Vaccine Manufacturing for its Effect of Inactivation, Splitting and Site of Manufacturing. Comparison of Influenza Vaccine Production Processes and teaches that four split and two whole inactivated virus (WIV) influenza vaccine bulks were produced and compared with respect to release criteria, stability of the bulk and haemagglutinin recovery. The inactivation of the virus was performed with either formaldehyde in phosphate buffer or with betapropiolactone in citrate buffer (See Title and Abstract). Based on the description, Kon et al. teaches the amended claim 1 as follows:
Kon et al. teaches a method of producing an inactivated influenza vaccine where the inactivated influenza virus H3N2 is the active product in the composition. Based on the Fig. 1, Kon et al. teaches (a) for the virus being a live virus harvested from the allantoic fluid and clarified by centrifugation, and incubated with the chemical inactive agents such as formaldehyde at a final concentration of 0.02% formalin (BPL (See Fig. 1 and page 3, paragraphs 1-3, and below), which teaches the composition is a liquid composition and it is obvious that the liquid solution is in a container as claimed. As for the “a mixture in a batch process”, Kon et al. teaches that “Six different influenza vaccine batches of bulk vaccine product were produced starting from one batch of clarified allantoic fluid” and “Good Manufacturing Practices (GMP) compliant facilities of Cantacuzino were used to produce the influenza vaccine batches” (See page 1, Materials & Methods), which would involve mixing the influenza virus with the inactivation agents. For example, Kon et al. teaches that the Formaldehyde inactivation (24 hr at 2–7°C) was performed at a final concentration of 0.02% formalin, whereas BPL based inactivation (24 hr, 18–22°C) was with a final BPL concentration of 0.1% (See page 4, paragraph 3), where a solution with a final concentration needs to be completely mixed.
As for (b) and (c), Kon et al. teaches that their inactivation process is based on the standard Intravacc protocols (See page 1, paragraph 5; Fig. 1., page 3 and below), where Intravacc is a Dutch vaccine research and development company (https://www.intravacc.nl/). For example, Kon et al. teaches that the “Formaldehyde inactivation (24 hr at 2–7°C) was performed at a final concentration of 0.02% formalin, whereas BPL based inactivation (24 hr, 18–22°C) was with a final BPL concentration of 0.1%” (See Fig. 1 and below;
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Page 4, paragraph 3), where the mixture incubating 24 hour teaches the incubating time “from 1-20 days” as claimed in claim 1 (c).
For the agitation time, Kon et al. teaches that the splitting inactivation is under stirring/agitation for 1 hr at 20°C (See page 4, paragraph 6), which is in the range of “…agitation for a period of 1-60 minutes after the contacting of step (a)” as claimed in claim 1 (b). Although Kon et al. does not explicitly teaches “…no further agitation is performed after the initial mixing of step (b)” (claim 1 (c)), however, it is a common knowledge in the art that the agitation/mixing time and incubation time of chemical viral inactivation is a critical, highly variable parameter in the inactivation process, which is specific to the type of virus, chemical used, concentration, pH and temperature. Therefore, one of ordinary skills would be able to test and optimize a “agitation time” as claimed through routine experimentation. This can be evidenced by many teachings from different groups as follows:
Sarkar et al. teaches that the inactivation was carried out at 37°C with constant agitation for 24 h with an intermittent change of the flask at 12 h interval (See page 11, left column, Materials and methods).
Sirasitthichoke et al. teaches that that pilot and manufacturing-scale tanks are typically operated at low agitation speed to minimize shear forces on the product (See page 170, right column, paragraph 1), and blend/agitation time is one of the critical parameters commonly employed to assess the mixing performance and the hydrodynamics of an agitated system. In general, blend time defined as the time required by the system to achieve a predetermined degree of homogeneity in a mixing process (See page 170, right column, paragraph 2).
Meer et al. teaches the higher agitation speed improved bacterial inactivation but did not influence viral inactivation (See page 3, Result).
Sanders et al. teaches that as compared to formaldehyde inactivation, BPL inactivation times are significantly shorter where minutes to hours can suffice in inactivating viral activity as compared to the days or months needed for formaldehyde inactivation (See page 64, paragraph 2).
Gillespie et al. teaches that traditional viral inactivation involves large holding tanks in which product is maintained at a target low pH for a defined hold time, typically 30–60 min (See Abstract).
Barbero et al. teaches that the formaldehyde-treated solution was mixed on a magnetic stirrer for 10 minutes. After sampling, the formaldehyde-treated viral solution was placed within a cooled incubator at 22°C ± 2°C. On Day 5 post addition of formaldehyde, the formaldehyde treated viral solution was filtered through a 0.2 μm filter and then placed in the incubator at 22°C ± 2°C again. On Day 10, after removing the 10-Day inactivation final sample, a volume of 1 % (of the weight of the final formaldehyde-treated viral solution) of 200 mM-sodium metabisulphite solution (2mM final concentration) was aseptically transferred into the PETO container containing the formaldehyde-treated viral solution. After mixing for 5 minutes on a magnetic stirrer, the neutralized inactivated viral solution is held at room temperature (20 to 25°C) for a minimum of 30 minutes. After sampling, the neutralized inactivated viral solution is stored at 5°C ± 3°C until further processing (See page 110, lines 24-34). Here the description teaches “the agitation for a period of 1-60 minutes” as claimed in claim 1 (b), and without mix for incubating from 1-20 day as claimed in claim 1 (c).
Accordingly, Sarkar, Sirasitthichoke, sanders, Gillespie and Meer teaches that the agitation/mixing time and incubation are based on different conditions. Barbero teaches a comparable agitation/mixing time as claimed where the incubation is continued for 10 days after the 10 min stirring/mixing.
Based on the evidence teaching above, one of ordinary skills would be able to test and optimize “agitation time” through routine experimentation based on a specific condition listed above. Also, Barbero teaches a mixing and incubation time as claimed in the base claim 1 (b) and (c).
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 4-5, they further require the mixing comprises inverting the container not more than 1, 2, 3, 4 or 5 times and including rocking, rotation, orbital shaking, or oscillation at certain time and speed for mixing. Kon et al. teaches that for the ether-tween split products, first Tween1 80 (polysorbate 80, Merck KGaA) was added to the bulk to a concentration of 1.25 mg/mL and then combined with an equal volume of ether (Diethyl Ether, Merck KGaA) while stirring at 4°C, and Fractions 3.1F and 3.1B were split by 1% Triton™ X-100 (Sigma-Aldrich) in presence of 500 mg/L Tween during stirring for 1 hr at 20°C (See page 4, paragraph 6), where the stirring is obviously involved in rocking, rotation, orbital shaking, or oscillation depending on the container/equipment used. Although Kon teaches a different stirring time (60 min), it would be obvious for one of ordinary skill in the art to test for an optimal inverting time, mixing times as claimed through routine experimentation.
As for the agitation speed at the period of incubation for virus inactivation, it also depends on the specific inactivation method being used and the characteristics of the solution or product being treated. This can be evidenced by Sirasitthichoke and Meer. Sirasitthichoke et al. teaches that pilot and manufacturing‐scale tanks are typically operated at low agitation speed to minimize shear forces on the product (See page 170, right column, paragraph 1) and to simulate the continuous Triton X‐100 addition used in the actual viral inactivation process, the agitation speed can be at 140 rpm (See page 173, left column). Meer et al. teaches the higher agitation speed improved bacterial inactivation but did not influence viral inactivation (See page 3, Result). Therefore, it would be obvious for one of ordinary skill in the art test an optimal agitation speed as claimed through routine experimentation.
Accordingly, the claimed inverting times, mixing time and agitation speed would have been obvious unless there is evidence showing that they produce unexpected results.
Regarding claim 7, Kon et al. teaches that their study aim is to evaluate the impact of different inactivation and splitting procedures on influenza vaccine product composition, stability and recovery to support transfer of process technology (See Abstract). The Fig. 1 and Table 1 of Kon et al. teach the inactivating virus method used by the Cantacuzino standard and the Intravacc standard (See page 3, Fig. 1 and above; table 4). Because of the virus inactivation process obviously involves a mixing step, one of ordinary skill in the art can develop a method to compare the mixing time of inactivation based on the two-standard system, Cantacuzino standard and the Intravacc standard, where the mixing time should be restricted in Cantacuzino standard because of GMP restriction (See page 2, Materials and Methods) because Sirasitthichoke et al. teaches that blend/agitation time is one of the critical parameters commonly employed to assess the mixing performance and the hydrodynamics of an agitated system. In general, blend time defined as the time required by the system to achieve a predetermined degree of homogeneity in a mixing process (See page 170, right column, paragraph 2).
Regarding claim 8, Kon et al. teaches that the inactivation of the virus is performed with either formaldehyde in phosphate buffer or with betapropiolactone in citrate buffer (See Abstract).
Regarding claims 9-10, Kon et al. teaches that Formaldehyde inactivation (24 hr at 2–7°C) was performed at a final concentration of 0.02% formalin, whereas BPL based inactivation (24 hr, 18–22°C) was with a final BPL concentration of 0.1% (See page 4, paragraph 3). As for the new amended “10 days” in claim 9, Barbero et al. teaches an incubation for 10 days (See page 110, lines 24-34).
Regarding claims 11-13, Kon et al. teaches the inactivated virus is influenza virus, an RNA virus, belongs to the Orthomyxoviridae family, which teaches claims 11-12. Although Kon does not teach the virus as claimed in claim 13, Sanders et al. teaches that there are six licensed viral vaccines that are inactivated with either formaldehyde or BPL. Formaldehyde is used for the inactivation of Poliovirus (PV), Hepatitis A Virus (HAV), Japanese Encephalitis Virus (JEV), and Tick-Borne Encephalitis Virus (TBEV) to generate vaccines. BPL is used for the inactivation of Rabies and Influenza virus vaccines (See page 49, paragraph 3). It would be obvious for one of ordinary skill in the art to include the inactivation vaccine of Poliovirus (PV), Hepatitis A Virus (HAV), Japanese Encephalitis Virus (JEV), or Tick-Borne Encephalitis Virus (TBEV) in Kon’s study, and the result would be predictable by using the two-standard system, Cantacuzino standard and the Intravacc standard, to performing the inactivation.
Regarding claim 14, Kon et al. teaches the main unit operation for purification was sucrose gradient zonal ultracentrifugation (See Abstract).
(New Rejection-necessitated by amendment) Claims 2 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Kon et al. (PLoS One. 2016 Mar 9;11(3): e0150700) as evidenced by Sarkar et al. (Biologicals. 2017 Jul; 48:10-23), Sirasitthichoke et la. (Biotechnol Bioeng. 2023 Jan;120(1):169-183), Sanders et al. (Strategies, Principles, and Control. 2014 Nov 28:45–80) and Gillespie et al. (Biotechnol J. 2019 Feb;14(2): e1700718), Meer et al. (Vox SanguinisVolume 111, Issue 2 pp. 127-134, May 11, 2016) and Barbero et al. (WO2017109223A1, published on June 29, 2017) as applied to claims 1 and 4-5, 14 above, and in view of Jenke et al. (Pharmaceutical outsourcing, May 28, 2014) as evidenced by Linked In ((https://www.linkedin.com/pulse/single-use-bags-bioreactor-real-world-5-uses-youll-jwief/#:~:text=Single%2Duse%20bags%20for%20bioreactors,technological%20innovations%20and%20regulatory%20shifts).
Claim 2 requires the chemical viral inactivating agent and the liquid composition comprising the virus is performed in a flexible bioreactor bag.
Claim 17 is directed to a method of claim1, wherein an interior surface of the container comprises ethylenvinylacetate (EVA).
Based on the description above, Kon et al. teaches a method of inactivating a virus comprising contacting a liquid composition, however, it is silent on the interior surface of the container comprises ethylenvinylacetate (EVA). Also, Kon’ s virus inactivation method is obvious performed in certain containers, but Kon does not specifically point out it is a flexible bioreactor bag.
Jenke et al. teaches that containers (also known as bags) are used to store final drug products, active pharmaceutical ingredients (APIs), and starting reagents and process intermediates used during the manufacturing of either the drug product itself or ingredients in that drug product. Additionally, sterile bags can be used in the manufacturing of biopharmaceuticals, either to store media and associated process solutions or as a bio-reaction vessel. It is common for such bags to be constructed from multi-layered polymeric films, where the film’s construction (number of layers, thickness of layers) and the choice of the plastics used in the layers are dictated by functional performance requirements for the bags. Sterile bags are typically rendered sterile via gamma irradiation. Common plastics used in such multilayered films include ethylene vinyl acetate (EVA) and polyethylene (PE), as they provide a relatively inert fluid contact layer and are relatively inexpensive (See Abstract). Jenke et al. also teaches the benefits of having the EVA in a container designed as C2 and compared the difference between C2 and C1, wherein the C2 is the container with three-layer composite with EVA as the solution contact layer and C1 is the container with four-layer composite consisting of ultra-low-density polyethylene (ULDPE) as the solution contact layer (See page 2, paragraph 3). Jenke et al. discloses that the migration will occur more quickly in material C2 than in material C1 given that material C2 has the EVA layer in direct solution contact (See page 3, paragraph 3), the release of acetic acid from material C2 is virtually instantaneous while the acetic acid release from material C1 is slower (See page 4, paragraph 1), and the larger release of acetic acid in film C2 occurs immediately as the EVA is the solution contact layer in the film (See page 5, paragraph 3). As for the application of the bioreactor bag, Jenke also teaches that the published data concerning the migration of extractables from two multi-layered films (PE, EVA, and EVOH layers) used in bio-processing solution bags have been examined with the intent of elucidating the migration mechanism. Because the films have different layer patterns, and because the films were tested before and after irradiation, the effect of film structure and irradiation on the migration of extractables, especially acetic acid, could be established (See page 8, paragraph 3). Also, the benefit of the bioreactor bag is described in the Linked In, it states that the single-use bags for bioreactors have become a cornerstone in biopharmaceutical manufacturing. They offer flexibility, reduced contamination risk, and faster turnaround times compared to traditional stainless-steel systems (See page 1).
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 introduce EVA and a bioreaction bag into Kon’s invention for the interior surface of the container. One of skill in the art would have been motivated to do so to apply the EVA of Jenke on the surface of the container for inactivating a virus, and introduce the bag in the inactivation process. There would be a reasonable expectation of success to develop a method of inactivating a virus in a container/bag with EVA based on the benefit taught by Jenke.
(New Rejection-necessitated by amendment) Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Kon et al. (PLoS One. 2016 Mar 9;11(3): e0150700) as evidenced by Sarkar et al. (Biologicals. 2017 Jul; 48:10-23), Sirasitthichoke et la. (Biotechnol Bioeng. 2023 Jan;120(1):169-183) and Sanders et al. (Strategies, Principles, and Control. 2014 Nov 28:45–80) and Gillespie et al. (Biotechnol J. 2019 Feb;14(2): e1700718), Meer et al. (Vox SanguinisVolume 111, Issue 2 pp. 127-134, May 11, 2016) and Barbero et al. (WO2017109223A1, published on June 29, 2017) as applied to claims 1 and 4-5, 7-14 above, and in view of Hobbs et al. (Chemical Engineering Journal 70 (1998) 93- 104).
Claim 3 is directed to a method of claim 2, wherein the mixing is performed under conditions that result in a modified Reynolds Number (Remod) of less than 1000.
Based on the description above, Kon et al. teaches a method of inactivating a virus comprising contacting a liquid composition, however, it is silent on the mixing condition on the Reynolds Numbers.
The Reynolds number (Re) is a dimensionless quantity that helps predict fluid flow patterns in different situations by measuring the ratio between inertial and viscous forces. At low Reynolds numbers, flows tend to be dominated by laminar (sheet-like) flow, while at high Reynolds numbers, flows tend to be turbulent (https://en.wikipedia.org/wiki/Reynolds_number). Hobbs et al. teaches that mixing is an essential component of nearly all industrial chemical processes, ranging from simple blending to complex multiphase reaction system for which reaction rate, yield and selectivity are highly dependent upon mixing performance (page 93, left column, paragraph 1). Hobbs et al. teaches that the Reynolds number for a laminar flow condition is less than 1000, and teaches that when the Reynolds number is less than 1000, such as 10, the work expended per unit volume passing through the mixer is proportional to the Reynold number, and the most energy efficient mixing is achieved at the lowest flowrates (See page 103, right column, paragraph 2; Bridging pages 103-104). In addition, Hobbs et al. uses the formula of (Re= (p< vx> D) /µ ) to calculate the Reynolds number under their study condition (See page 94, left column). Although the formula is not identical to the formula claimed in the instant application, the details of the system geometry and fluid properties disclosed in table 1 (See page 94 and below) are comparable to the formula elements as claimed.
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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 teaching of Kon and Hobbs to arrive at an invention as claimed. One of skill in the art would have been motivated to do so because Hobbs teaches that the most energy efficient mixing is achieved at the Reynolds number for a laminar flow condition being less than 1000. There would be a reasonable expectation of success to develop a method of inactivating a virus mixing of the chemical viral inactivating agent and the liquid composition by determining and control the Reynolds number at less than 1000.
(New Rejection-necessitated by amendment) Claims 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Kon et al. (PLoS One. 2016 Mar 9;11(3): e0150700) as evidenced by Sarkar et al. (Biologicals. 2017 Jul; 48:10-23), Sirasitthichoke et la. (Biotechnol Bioeng. 2023 Jan;120(1):169-183) and Sanders et al. (Strategies, Principles, and Control. 2014 Nov 28:45–80) and Gillespie et al. (Biotechnol J. 2019 Feb;14(2): e1700718), Meer et al. (Vox SanguinisVolume 111, Issue 2 pp. 127-134, May 11, 2016) and Barbero et al. (WO2017109223A1, published on June 29, 2017) as applied to claims 1 and 4-5, 7-14 above, and in view of Coffman et al. (WO 2015/158776 A1, published on Oct. 22, 2015) as evidenced by Merchuk et al. (Encyclopedia of Industrial Biotechnology, 15 April 2010).
Regarding claims 15-16, they require the specific work volume by percentage in the container.
Kon et al. teaches a method of inactivating a virus comprising contacting a liquid composition and teaches their inactivated process is based on the GMP guideline of Cantacuzino and protocol of Intravacc. Although they do not disclose a details protocol regarding the guidelines, the optimized inactivated solution (including the virus and the inactivating agent) should be taught in the GMP and the company’s guidelines.
Nevertheless, Coffman et al. teaches that the ratio of the internal volume of the pre-treatment hold reservoir to the internal volume of the treatment vessel is 0.003 to 0.06. For example, the internal volume of the pre-treatment hold reservoir is 0.63 ml to 1.4 l, and the internal volume of the treatment vessel is 200 ml to 25 l (See page 8, lines 1-7), where the pre-treatment is comparable to the liquid composition comprising the virus and the chemical viral inactivating agent, and the ratio is between 0.3% to 6%. Because Coffman's method for inactivating virus is part of the manufacture process, the ratio of the total volume and the treated composition is under manufacture's requirement as claimed in claim 16.
For the limitation of the" the volume calculated to provide the minimum gas-liquid interface size for the container" as claimed in claim 15, Coffman et al. does not explicitly describe the gas- liquid interface size in their invention. However, Coffman et al. teaches that the bioreactor can be air-lift bioreactor and " ... the biological product can be produced by a homogeneous process, e.g. suspension culture based on use of a stirred-tank bioreactor, air-lift bioreactor, or wave bioreactor ... " (See page 13, lines 27-30), where the air-lift bioreactor uses injected air to create a liquid circulation pattern, generating mixing and mass transfer (like oxygen) without mechanical stirrers, relying on the gas-liquid interface (the bubble surface) for efficient gas exchange, crucial for aerobic cultures and sensitive cells due to low shear and energy. This can be evidenced by the study of Merchuk. Merchuk et al. teaches that an airlift reactor (ALR) is a gas–liquid or gas–liquid–solid pneumatic contacting device that is characterized by fluid circulation in a defined cyclic pattern through channels built specifically for this purpose. In ALRs, the content is pneumatically agitated by a stream of air or by other gases (See page 1, left column, paragraph 1). Merchuk et al. teaches ALRs are superior to traditional stirred-tank fermenters (STRs) for many processes based on biomass growth, and provides the homogeneity of the stress forces and mechanical simplicity (See page 2, right column). Merchuk et al. also teaches that ALR requires a minimum liquid volume for proper operation. Indeed, the changes in liquid volume in these reactors are limited to the region of the gas separator, because the liquid height must always be sufficient to allow liquid recirculation in the reactor and must therefore be above the separation between the riser and the downcomer (See page 3, right column), which indicates to adjust the volume of the liquid to minimize the gas-liquid interface size. One of the advantages of the directionality of flow in ALRs is the improved fluidization capacity.
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 from Kon and Coffman/ Merchuk to arrive at an invention as claimed. One of skill in the art would have been motivated to do so based on the advantage that the airlift reactor offered. There would be a reasonable expectation of success to develop such a method for inactivating a virus by adjusting the volume of the liquid composition based on the size of the container as claimed.
Responses to Applicant’s Remarks
Applicant’s arguments filed on Mar. 16, 2026 has been received and fully considered.
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 arguments and amendments.
3. Applicant’s arguments on rejection under 35 U.S.C. § 103 is not found persuasive as follows:
1). Applicant argued that Kon teaches a standard inactivation process for influenza virus but does not recognize the problem of yield loss due to mechanical stress-induced precipitation. A person of ordinary skill in the art, following the teachings of the art (e.g., Sarkar et al., cited by the Examiner), would be motivated to increase or maintain agitation to ensure complete inactivation, not eliminate it (See Remarks, page 7, paragraph 3).
Applicant’s argument is not persuasive.
First, the argument “…recognize the problem of yield loss due to mechanical stress-induced precipitation” does not limit in the instant claims.
Second, as mentioned above, it is a common knowledge in the art that the agitation/mixing time of chemical viral inactivation is a critical, highly variable parameter in the inactivation process, which is specific to the type of virus, chemical used, concentration, pH and temperature. Therefore, one of ordinary skills would be able to test and optimize a “agitation time” as claimed through routine experimentation. Also, Kon teaches a stirring time at 1 hr (See page 4, paragraph 5). In addition, the new added prior art, Barbero et al., teaches a mixing time for 10 minutes and then the formaldehyde-treated viral solution was incubated for 10 days (See page 110, paragraph 5).
Third, in the same paragraph, applicant also allegedly argued that eliminating constant agitation resulted in a nearly five-fold increase in virus recovery (from 8% to over 50%), a dramatic and unexpected result (see published application, FIG. 5 and para. [0136]). This is not persuasive because the instant amended claims do not require the yields of the recovery. Also, the instant Fig. 5 in the drawing filed on 09/02/2025 and the instant specification filed on 09/02/2025 shown that Fig. 5 is an SDS-PAGE data and no indication on the yield percentage.
2). Applicant argued that a person of ordinary skill in the art would not have
had a reasonable expectation of success when combining Kon and Jenke, as there was no teaching that an EVA surface would be particularly advantageous for solving the previously unrecognized problem of mechanical stress-induced precipitation of viruses during an inactivation process based on example 6 (See Remarks, page 8, paragraph 2).
Applicant’s argument is not persuasive.
First, Jenke et al. teaches an advantage to use the EVA as interior surface of the
Container/bag by stating that the migration will occur more quickly in material C2 than in material C1 given that material C2 has the EVA layer in direct solution contact (See page 3, paragraph 3). 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 introduce EVA and a bioreaction bag into Kon’s invention for the interior surface of the container.
Second, the base claim 1 does not have a limitation on “a bag with an
LLDPE surface” as argued.
Third, Jenke is used here to support a teaching for a specific claim. It is applicable to combine it with the primary references and other prior arts for the rejection.
3). Applicant argued that the motivation in Hobbs is entirely different from that of the Applicant (See Remarks, page 9, paragraph 2).
Applicant’s argument is not persuasive.
The instant claims do not have limitation for a motivation. Hobbs teaches that the most energy efficient mixing is achieved at the Reynolds number for a laminar flow condition being less than 1000, which is appliable to be a support art to combine with Kon for the specific claim rejection.
4). Applicant argued that the Examiner improperly equates the technology of an airlift bioreactor (Coffman/Merchuk) with the wave bag bioreactor of the present invention (See Remarks, bridging pages 9-10).
Applicant’s argument is not persuasive.
Both claims 15 and 16 are dependent on the instant claim 1, where the base claim 1 does not have limitations for a specific container such as airlift bioreactor or wave bag bioreactor. Accordingly, it is applicable for Coffman et al. and Merchuk et al. to be used as a support to the primary reference to support the rejection.
5). Applicant argued that the present application discloses the surprising and unexpected discovery that minimizing or eliminating mechanical stress after a brief initial mixing period dramatically increases the recovery of inactivated virus by preventing precipitation. This finding directly teaches away from the conventional wisdom in the art, which holds that continuous and thorough agitation is necessary to ensure complete viral inactivation (See Remarks, page 7, paragraph 1).
Applicant’s argument is not persuasive.
First, the instant application does not have the limitation “minimizing or eliminating mechanical stress after a brief initial mixing period dramatically increases the recovery of inactivated virus by preventing precipitation” in the claims.
Second, as an initial matter, “the burden of showing unexpected results rests on one who asserts them. Thus, it is not enough to show that results are obtained which differ from those obtained in the prior art: that difference must be shown to be an unexpected difference.” In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972) (citation omitted). Moreover, “[i]t is well settled that unexpected results must be established by factual evidence. Mere argument or conclusory statements in the specification does not suffice.” In re De Blauwe, 736 F.2d 699, 705 (Fed. Cir. 1984) (citation omitted).
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