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 July 01, 2026. Claims 1-5 and 7-17 are pending and currently examined.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
IN GENERAL. —The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
(New Rejection) Claim 1 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The amendments to the base claim 1 introduce new matter.
The amended base claim 1 recites a phrase “wherein recovery of virus is at least 50% of virus particles of the live virus of (a)” that were not disclosed in the originally filed specification. Therefore, the base claim 1 introduces new matter. The instant specification disclosed that in some embodiments, the recovery of virus is at least 30%, 40%, 50%... 500%, or more, greater than the recovery of virus under standard mixing conditions or standard inactivation procedures (See e.g., [0047]), where the recovery rate is compared with the live viruses.
Therefore, the base claim 1 introduces new matter.
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 rejection-maintained with edition) 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) in view of Barbero et al. (WO2017109223A1, published on June 29, 2017) and Gillespie et al. (Biotechnol J. 2019 Feb;14(2): e1700718) as evidenced by Cannonwater-downloaded 2025 (https://cannonwater.com/water-treatment-equipment/mixers/static-inline-ixers/?srsltid=AfmBOooEaaEjMtRswv9anZ9XphTE_f2_DxaGi8b7iyAgoSfpNR6npwla).
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), wherein recovery of virus is at least 50% of virus particles of the live virus of (a).
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; Page 4, paragraph 3), where the mixture incubating 24
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hour teaches the incubating time “from 1-20 days” as claimed in claim 1 (c). At the same time, Kon teaches the recovery rates after the inactivation by Formaldehyde and Beta-Propiolactone in Table 5 (See page 8, and below), where, for example, the inactivated product (formaldehyde) FE can be at 72% recoveries in product 5.1 after SF, which is above the 50% as claimed in claim 1 (c).
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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).
As for the limitation of “incubating the mixture for a period of time from 1 to 20 days to inactivate the virus”, after the agitation 1hour, the virus is inactivated for 24-hr at 2–7°C with formaldehyde or for 24 hr at 18–22°C with BPL (See page 4, paragraph 3), which can be considered as 1 day as claimed.
Nevertheless, Barbero teaches that 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 (See page 110, lines 24-34), which indicates that the incubation is 10 days and teaches the claimed incubation time for 1-20 days.
Barbero also teaches that the advantage of their invention is that related methods of producing said vaccines and compositions are very efficient and provide pure compositions largely devoid of impurities, in particular protamine sulphate, allowing for high volume production of vaccines (See page 8, lines 25-29).
As for the further limitation in the claim 1 (c) at “wherein no further agitation is performed after the initial mixing of step”, Kon teaches an initial agitation/stirring step for 1hour (See page 4, paragraphs 5-6) with the chemical viral inactivation agents, Tween 80 or Triton™ X-100. After the agitation 1hour, the virus is inactivated for 24-hr at 2–7°C with formaldehyde or for 24 hr at 18–22°C with BPL (See page 4, paragraph 3). However, Kon does not describe any additional agitation/stirring in the 24-hr inactivation period. Here it is reasonable to consider that there is no further agitation/stirring for the 24 hours after the 1 hour stirring/agitation with the inactivation agent. Here it can teach the “no further agitation is performed after the initial mixing” as claimed in the claim (c).
Nevertheless, Gillespie teaches a lab-scale in-line low pH viral inactivation system with a static mixer by adding the acid (See Abstract; pages 4, paragraphs 3-4). Gillespie teaches that in-line static mixer viral inactivation system can be much shorter than traditional viral inactivation operations and can be integrated into a continuous manufacturing process (See page 2, left column; See Figure 1, page 2 and below). Because there is no moving part in the static mixer, so no agitation can be applied. This can be evidenced by the product description from Cannonwater. Cannonwater teaches that the static inline mixer allows for inline mixing or blending of water and chemicals in the pipeline. They do not have moving parts and use the flow energy of water streams for mixing chemicals with water. They are easy installation and low operation cost (See page 1).
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It would have been prima facie obvious to a person with ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Kon, Barbero and Gillespie to arrive at an invention as claimed. One of skill in the art would be motivated to do so based on the benefit that the in-line static mixer provided and the inactivation incubation time that Barbero provided. There would have been a reasonable expectation of success to develop a method producing an inactivated viral vaccine as claimed.
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 Tween 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. As for the stirring time and speed, it would be obvious for one of ordinary skill in the art to test for an optimal inverting time, mixing times and a 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 10 days, 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, Barbero teaches that the inactivated virus is a Chikungunya virus, a positive-sense, single-stranded RNA virus from the genus Alphavirus, family Togaviridae(See page 1, lines 26-27). It would be obvious for one of ordinary skill in the art to introduce the Chikungunya virus into Kon’s study, and the result would be predictable based on the teachings from Kon and Barbero.
Regarding claim 14, Kon et al. teaches the main unit operation for purification was sucrose gradient zonal ultracentrifugation (See Abstract).
(Previous rejection-maintained with edition) 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) in view of Barbero et al. (WO2017109223A1, published on June 29, 2017) and Gillespie et al. (Biotechnol J. 2019 Feb;14(2): e1700718) as evidenced by Cannonwater-downloaded 2025 as applied to claims 1 and 4-5, 7-14 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.
(Previous rejection-maintained with edition) 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) in view of Barbero et al. (WO2017109223A1, published on June 29, 2017) and Gillespie et al. (Biotechnol J. 2019 Feb;14(2): e1700718) as evidenced by Cannonwater-downloaded 2025 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.
(Previous rejection-maintained with edition) 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) in view of Barbero et al. (WO2017109223A1, published on June 29, 2017) and Gillespie et al. (Biotechnol J. 2019 Feb;14(2): e1700718) as evidenced by Cannonwater-downloaded 2025 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 detailed 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 July 01, 2026 has been received and fully considered, and the declaration filed on July 01, 2026 also has been received and fully considered.
Applicant’s arguments on rejection under 35 U.S.C. § 103 is not found persuasive as follows:
1. Applicant allegedly mentioned their amendment is based on the Fig. 5 (See Remarks, page 5). However, Fig. 5 cited here is inconsistent with the Fig. 5 that was listed in the Drawing filed on 09/02/2025).In addition, Kon teaches the same steps as claimed in the base claim 1, so, the newly added limitation of the “recovery of virus is at least 50% of virus particles” should be achieved by the same steps.
2. Applicant argued that the references of record do not teach or fairly suggest intentionally omitting further agitate during an incubation of 1 to 20 days (See Remarks, page 6).
The argument is not persuasive because the instant claims do not cite a limitation if the “no further agitation is performed after the initial mixing” is performed “intentionally” or not. In addition, Kon 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), which does not explicitly recite that additional agitation occurs during the incubation step. Therefore, there is no evidence that additional agitation occurred.
3. Applicant next argued against references of Sarkar, Sirasitthichoke, Sanders, Gillespie, Meer and Barbero (See Remarks, page 7).
The argument is not persuasive.
1). It is applicable to use Sarkar, Sirasitthichoke, Sanders, Gillespie, Meer and Barbero as evidence to show the agitation time including the “no further agitation is performed after the initial mixing” is condition-depended and can vary depending on the types of chemical viral inactivating agent, pH, viral strains and equipment.
2). The references of Sarkar, Sirasitthichoke, Sanders, and Meer are not used in the current action. Thus, the arguments for these references are moot.
In addition, Barbero used in the current office action is only for a specific limitation at “incubating the mixture for a period of time from 1 to 20 days to inactivate the virus” as claimed in the claim 1 (c), thus, all the argument for the agitation regarding Barbero is moot.
4. Applicant argued that Barbero’s protocol [at pages 110, lines 24-34] did use agitation during the multi-day incubation at 22 °C based on Dr. Schlegl’s declaration as a co-inventor (See Remarks, page 7, paragraph 2).
The argument is considered and accepted based on the declaration of Dr. Schlegl as one of Barbero’s inventors. Therefore, Barbero used in the current action is only for teaching the incubation time, and not for the agitation rejection.
5. Applicant argued that without recognizing the adverse effects of even low agitation on virus recovery, the skilled artisan had no reason to consider omitting agitation during incubation, nor could they have expected to recover of at least 50% of input virus particles by doing so. As Dr. Schlegl explains, the skilled artisan considering the references of record would not have recognized that the mechanical stress even low rpm agitation places on virus particles during prolonged (e.g., 1-20 days) incubation could limit viral recovery after inactivation (See Remarks, page 8).
The argument is not persuasive.
First, “recognizing the adverse effects of even low agitation on virus recovery” and “recognizing the mechanical stress” are not the limitations in the instant claims.
Second, Gillespie’s in-line static mixer viral inactivation system does not have mechanical agitation.
Lastly, the prior art is not required to provide a reason to omit agitation. If the prior art does not teach agitation during the incubation step, then the prior art meets the limitation “wherein no further agitation is performed after the initial mixing of step (b)”.
6. Applicant argued that the surprising ability to reliably recover a given virion after inactivation by omitting agitation during incubation is an unexpected result supporting nonobviousness (See Remarks, page 9).
The argument is not persuasive because the prior arts of Kon, Barbero and Gillespie teaches their method also provided a reliable recovery after the viral inactivation process. For example, the Table 5 (see below, Kon) shows at least 50% recovery results in their study. Also, based on the description above, Kon teaches the same steps as claimed in the base claim 1, so, the outcome of at least 50% viral recovery should be the same.
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). 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). Applicant’s attention is directed to MPEP 716.02(b)-(e) for how unexpected results can be established. E.g., 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). Here, applicant has not provided sufficient information for the Office to 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.
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7. Applicant argued the references of Jenke, Hobbs and Coffman for not remedying the alleged deficiencies in the base claim 1.
The argument is not persuasive.
The references of Jenke, Hobbs and Coffman are used for addressing a specific limitation as claimed. It is appropriate to combine the teachings of Kon, Barbero and Gillespie with Jenke, Hobbs and Coffman to teach a specific limitation in the claims.
8. The declaration provided by Dr. Robert Schlegl has been reviewed and fully considered. However, the declaration is not persuasive at present as follows:
1). The declaration on the efforts for determine the virus sensitivity to the mechanical stress is recognized (See item 8) is not found persuasive. However, one of the references, Gillespie, teaches an in-line static mixer system that does not involve mechanical stress agitation.
In addition, the declaration is focused on the chemical viral inactivating agent, formaldehyde, however, the claimed chemical viral inactivating agent in the base claim 1 is a generic agent for any chemical viral inactivating agent.
2). The declaration on the recovery rate and the surprising results by omitting agitation during the longer incubation (See items 9-10) is not found persuasive. For example, Kon’s method teaches a comparable virus recovery (See Table 5 above), and Kon further teaches same steps as claimed in the base claim 1, thus the alleged unexpected viral recovery rate cannot be considered as an unexpected result.
In addition, as an initial matter, “the burden of showing unexpected results rests on he 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). Applicant’s attention is directed to MPEP 716.02(b)-(e) for how unexpected results can be established. E.g., 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). Here, there is no sufficient information for the Office to 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.
3). Regarding the declaration of item 11, the references cited by the office action provided all the elements as claimed. See the descriptions above in the current office action regarding rejections under 35 U.S.C. § 103.
4). Regarding the declarations on items 12-14, the references of Sarkar, Sirasitthichoke, van der Meer and Sanders were removed from the current office action. The argument for the references is moot.
5). The declaration on Barbero’s teaching as one of Barbero’s inventor regarding the agitation is highly recognized and accepted (See items 15-17).
6). Regarding the declaration of Gillespie’s teaching on item 18, the instant specification discloses that the loss due to precipitation was determined to result from inactivation process parameters, including mechanical stress resulting from agitation of the inactivation mixture (See 0004), which indicates the agitation is a mechanical process. However, Gillespie teaches an in-line static mixer system that is not involve in mechanical agitation.
7). Regarding the declarations on item 19, the instant claims does not cite a limitation on “any reason to be concerned with the effects of agitation on virus particle integrity or precipitation” as declared.
8). The declarations in items 20-21 are difficult to read. A clear copy needs to be submitted. Nevertheless, determining agitation condition and incubation time for viral inactivation is a routine technology in the art, one of ordinary skills would be able to test for an optimal condition for the viral activation through routine experimentation unless there is evidence showing that they produce unexpected results, where a sufficient information need to be provided for the Office to 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.
Conclusion
No claims are allowed.
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.
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/RUIXUE WANG/Examiner, Art Unit 1672
/NICOLE KINSEY WHITE/ Primary Examiner, Art Unit 1672
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