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 Mar. 10, 2026. Claims 1, 3, 7-15, 17, 19-23, 30 and 35 are pending. Claims 13-15, 17, 19-23 and 30 are withdrawn. Claims 1, 3, 7-12 and 35 are currently examined.
Claim Objection
(Previous objection- withdrawn) Claim 8 is objected to because of the following informalities: the phrase recited in claim 8 at “the cell is Madin-Darby canine kidney (MDCK) cells” should be “the cell is a Madin-Darby canine kidney (MDCK) cell” or “the cells are Madin-Darby canine kidney (MDCK) cells”.
This objection is withdrawn in view of the amendment filed on Mar. 10, 2026.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
(Previous rejection- withdrawn) Claims 1, 3-5, 7-12 and 35 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
This rejection is withdrawn in view of the argument and amendment filed on Mar. 10, 2026.
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(Previous rejection- withdrawn) Claims 1, 3-5 and 7-12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly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This rejection is withdrawn in view of the amendment filed on Mar. 10, 2026.
(Previous rejection- withdrawn) Claims 1, 3-5 and 7-12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01.
This rejection is withdrawn in view of the amendment filed on Mar. 10, 2026.
(New rejection) Claims 1, 3, 7-12 and 35 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.
The base claim 1 (f)-(i) recites “selecting a value b from 100, 200, 300, 400, 500, 600, 700, 800, and 900 such that an absolute difference TPOV – b is minimized” that renders the claim indefinite. It is unclear what the “value b” is. Also, there is no unit for the value b at 100, 200, 300, 400, 500, 600, 700, 800, and 900.
In addition, the term “minimized” in the base claim 1 (f)-(i) render the claims indefinite. It is not clear how the absolute difference TPOV – b is minimized and what the result is. The specification also does not provide descriptions on how the “minimized” effects are approached. The recitation “minimized’ is a relative term having no definite meaning and it is unclear how “minimized” is determined or what degree of minimizing is necessary. Applicant has not defined the degree of minimization (e.g., 2-fold, 5-fold, etc.).
The specification does not define “minimized” such that one of ordinary skill in the art would know if the absolute difference TPOV – b is minimized. Accordingly, one of ordinary skill in the art will not know the metes and bounds of the claim.
The claim 7 recites the term “a condition permissive” that render the claim indefinite. It is unclear what the condition for permissive replication is. For purposes of compact prosecution and applying prior art, the claim 7 was interpreted herein to encompass a condition permissive that is the condition that the influenza virus can propagate.
It is noted any interpretation of the claims set forth above does not relieve Applicant of the responsibility of responding to this rejection. If the actual interpretation of the claims is different than that posited by the Examiner, additional rejections and art may be readily applied in a subsequent final Office action.
Claim 11 recites a term “different conditions” that render the claim indefinite. It is unclear what the different condition is. The instant specification also does not provide definition for the “different conditions”.
Accordingly, one of ordinary skill in the art will not know the metes and bounds of the claim.
(New rejection) Claims 1, 3, 7-12 and 35 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01.
The base claim 1 (c) omit a step on how to use TPQV to determine the CTAB treatment concentration from the a CTAB stock.
Claim Rejections - 35 USC § 112 (Scope of Enablement)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(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.
(Previous rejection- withdrawn) Claims 1, 3 and 7-12 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for purifying a surface antigen protein of HA (hemagglutinin) from a cultured influenza virus using a detergent CTAB, does not reasonably provide enablement for a method for purifying any surface antigen protein of any type (active or inactive) influenza virus using any type of detergents.
This rejection is withdrawn in view of the amendment filed on Mar. 10, 2026.
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) Claims 1, 3, 7-12 and 35 are 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 phrases “separating solubilized components from residual sub-viral particles to obtain the HA”, where the “separating solubilized components” were not disclosed in the originally filed specification. 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- withdrawn) Claims 1, 3 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Phelan et al. (J Biol Stand. 1980;8(3):233-42).
This rejection is withdrawn in view of the amendment filed on Mar. 10, 2026.
(New Rejection-necessitated by amendment) Claims 1, 3-5, 12 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Wolff et al. (EP1982727A1, published on Oct. 22, 2008).
The base claim 1 is directed to a method for purifying hemagglutinin (HA) from an influenza virus using cetyltrimethylammonium bromide (CTAB), the method comprising: (a) providing an influenza virus sample; (b) obtaining a total protein quantification value (TPQV) in ug/mL for a dose of the influenza virus sample by performing a total protein quantification assay on the dose of the influenza virus sample; (c) determining, based on the TPQV, a CTAB treatment concentration for CTAB treatment of the influenza virus sample from a CTAB stock; (d) preparing a CTAB treatment solution by diluting the CTAB stock to the CTAB treatment concentration; (e) treating the sampled influenza virus with the CTAB treatment solution at the CTAB treatment concentration; and (f) separating solubilized components from residual sub-viral particles to obtain the HA, wherein determining the CTAB treatment concentration comprises:(i) selecting a value b from 100, 200, 300, 400, 500, 600, 700, 800, and 900 such that an absolute difference │TPQV - b│ is minimized; and(ii) determining the CTAB treatment concentration by (A) multiplying the TPQV by a factor a, (B) dividing by the selected value b,(C) adjusting based on a concentration c of the CTAB stock, and(D) scaling based on the volume of the influenza virus dose used for obtaining the TPQV compared to the volume d of the influenza virus sample of step (a) that is to be treated with CTAB, wherein a is 0.005% (v/v) to 0.100% (v/v), c is the concentration of the CTAB stock (% (v/v)), and d is the volume of the influenza virus sample of step (a).
Wolff et al. teaches a method for purification of viral membrane proteins based on treating influenza virions in an aqueous medium with a cationic detergent to selectively solubilize components, and separating the resulting solubilized components from residual sub-viral particles (See [0001] and [0009]), where the viral membrane proteins are the surface antigen proteins neuraminidase (NA), hemagglutinin (HA) and the ion channel (M2) (See [0001] to [0002]), which teaches using the detergent to purify the surface antigen protein as claimed. Wolff et al. also teaches that Cetyltrimethylammonium Bromide (CTAB) is one of the surfactants (See e.g., column, claim 27).
Accordingly, Wolff teaches a method of purifying the HA of influenza using the CTAB as follows:
(a) use the influenza sample.
(b) obtaining a total protein quantification value where total protein was monitored by UV-adsorption at 280 nm (See [0020]). It is obvious that the OD280 value can be used to calculate the protein concentration at unit ug/ml. This can be evidenced by Thermoscientific (https://documents.thermofisher.com/TFS-Assets/BID/Technical-Notes/spectrophotometric-determination-protein-concentrations-280nm-technote.pdf). Thermoscientific teaches that at 280 nm wavelength, the aromatic amino acids tryptophan (Trp) and tyrosine (Tyr) exhibit strong light absorption, and to a lesser extent cysteine groups forming disulfide bonds (Cys–Cys) also absorb. Consequently, absorption of proteins and peptides at 280 nm is proportional to the content of these amino acids (See page 1, left column), and the proteins will absorb UV light in proportion to their concentrations. This relationship has been exploited for the spectrophotometric determination of protein concentrations, and it is defined by the Beer–Lambert law (or Beer’s law). Beer’s law describes the dependence of a protein’s absorbance on its absorptivity coefficient, its concentration, and the pathlength of the incident light: Equation 1, A = εcL where: A: absorbance of the sample (unitless), ε: molar extinction coefficient or molar absorptivity of the protein (M–1 cm–1), c: concentration of the protein (molar units, M), L: light pathlength (cm). The protein concentration based on the measured absorbance at 280 nm can be easily derived from the equation above (See page 2, left column). Also, the description above teaches the claim 12 that requires the TPQV of the sampled influenza virus is 50 μg/mL to 950 μg/mL. Based on the total protein’s OD280 value and the sample amount, one of skilled in the art can achieve a claimed concentration through routine experimentation.
(c) Although Wolff does not explicitly point out to use the total protein result to determine the CTAB concentration, Wolff teaches a method to detect total protein (See [0020]), teaches to modify a detergent concentration (See [0083]), where the detergent comprises Cetyltrimethylammonium Bromid (CTAB). Thus, one of skilled in the art can calculate the CTAB based on the protein concentration and the stock solution of CTAB. This can be evidenced by ResearchGate ( https://www.researchgate.net/post/How-do-you-choose-the-detergent-concentration-for-protein-purification). The ResearchGate teaches that one detergent micelle can solubilize about 10 molecules of lipid. If you assume a 1 mg/ml membrane protein solution to also contain about 1 mg/ml lipid, and the average molecular mass of lipids to be 750 Da, the solution is about 1.3 mM in lipid and you need 130 μM micelles to solubilize it. Thus, you need the total micelle concentration to be 230 μM. To calculate the amount of detergent, you need to multiply this with the aggregation number (number of detergent molecules per micelle) \ bar{m} and then add the critical micellar concentration (cmc) of the detergent. For example, CTAB has a cmc of 1 mM, a \bar{m} of 170 molecules per micelle and a Mr. 364.5 Da. Thus, to solubilize 1 mg/ml membrane protein, you need 40.1 mM (14.9 mg/ ml) of CTAB (See bridging pages 7 and 8).
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.”). Since Wolff et al. teaches a modified detergent concentrations for purifying the viral surface protein (See [0083]), one of ordinary skills would be able to test for an optimal concentration of CTAB through routine experimentation. Therefore, the claimed determining CTAB treatment concentration through TPQV would have been obvious unless there is evidence showing that they produce unexpected results.
(d) to (e), Wolff teaches that dilute a CTAB solution from a stock to treat the sample of influenza virus by stating that the present invention provides new methods wherein the host cells expressing viral membrane proteins recombinantly or host cells infected with virus such as influenza and propagating the same are treated with surfactants for membrane solubilization of said host cells (See Abstract; [0009]), where the preferred surfactant is a combination of cetyltrimethylammonium bromide (CTAB) as cationic surfactant and polysorbate, e.g. Tween 20 or Tween 80, as non-ionic surfactant (See [0069]), and the polysorbate 80 (0,025 %, w/v final conc.) and cethyltrimethylammonium bromide (CTAB) (0.05 %, w/v final conc.) can add to the sediment for overnight incubation at 4 °C while agitating to solubilize the viral membrane protein from the lipid membranes of the cellular and viral component (See [0078]), where the 0.05 %, w/v final conc of CTAB indicates a dilution from a stock solution. For example, Wolff teaches that the modified detergent concentrations can be: a. Final detergent concentrations: Polysorbate 80: 0.5% Cetyltrimethylammonium Bromid: 1.0% b. Final detergent concentrations: Polysorbate 80: 0.0375% Cetyltrimethylammonium Bromid: 0.075% c. Final detergent concentrations: Polysorbate 80: 0.05% Cetyltrimethylammonium Bromid: 0.1% d. Final detergent concentrations: Polysorbate 80: 0.1 % Cetyltrimethylammonium Bromid: 0.2% (See [0083]), which indicates a solution preparation and a treatment concentration dilution. In addition, based on the section 2144.05 of the MPEP described above, the claimed preparing and treating CTAB concentration in base claim 1 (d) to (e) would have been obvious unless there is evidence showing that they produce unexpected results.
(f) Wolff teaches that the method is based on treating influenza virions in an aqueous medium with a cationic detergent to selectively solubilize components, and separating the resulting solubilized components from residual sub-viral particles (See [0009]), where the solubilize components can be the HA (See [0002]).
As for the (f)-(i) and (f)-(ii), although Wolff et al. does not explicitly teach a calculation steps for determining a value b, CTAB treatment concentration, dividing by the selected value b, Wolff et al. teaches a serial dilution of the modified detergent concentrations: a. Final detergent concentrations: Polysorbate 80:0.5%, Cetyltrimethylammonium Bromide: 1.0%; b. Final detergent concentrations: Polysorbate 80: 0.0375%, Cetyltrimethylammonium Bromide: 0.075%; c. Final detergent concentrations: Polysorbate 80: 0.05%, Cetyltrimethylammonium Bromide: 0.1%; d. Final detergent concentrations: Polysorbate 80: 0.1 %, Cetyltrimethylammonium Bromide: 0.2% (See [0083]), which indicates that the detergent concentration can be modified. At the same time, Wolff et al. teaches that the cell culture includes the total protein that is monitored by UV-absorption at 280 nm (See [0020]), which indicates that the total protein and viral protein can be detected by the UV-absorption. Since calculating concentration based on a sample concentration such as influenza virus and a detergent concentration such as CTAB stock concentration is a routine technique in the art, one of skilled people in the art can optimize a concentration through routine experimentation. This can be evidenced by ResearchGate. It teaches a way to calculate the concentration of CTAB at “to calculate the amount of detergent, you need to multiply this with the aggregation number (number of detergent molecules per micelle) \ bar{m} and then add the critical micellar concentration (cmc) of the detergent. For example, CTAB has a cmc of 1 mM, a \bar{m} of 170 molecules per micelle and a M, of 364.5 Da. Thus, to solubilize 1 mg/ml membrane protein, you need 40.1 mM (14.9 mg/ ml) of CTAB” (See bridging pages 7 and 8). Although the calculation is not identical to the claimed method for the base claim 1 (f) (i) and (ii), it is reasonably to be considered as a comparable calculation method because ResearchGate discloses that this calculation uses a lot of hand waving, but predicts experiments quite accurately (See page 8).
In addition, based on the section 2144.05 of the MPEP described above, calculating the detergent treatment concentration based on a sample protein concentration and the detergent’s stock solution is not a patentable limitation except 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 claim 3, Wolff et al. teaches using the UV-adsorption at 280 nm to detect the total protein including the viral surface antigen proteins in the influenza A virus infected MDCK cells (See [0020]), which does not require to use SRID.
(New Rejection-necessitated by amendment) claims 7-10 are rejected under 35 U.S.C. 103 as being unpatentable over Wolff et al. (EP1982727A1, published on Oct. 22, 2008) as evidenced by BiteSize Bio (https://bitesizebio.com/13680/how-to-passage-cells/#:~:text=If%20you%20are%20splitting%20cells,3), and Sullivan et al. (Proanalytics, Posted on October 21, 2024 by David Koechlein, https://pro-analytics.net/continuous-centrifuge-prevent-high-density-cell-culture-fouling-optura-spy/?srsltid=AfmBOoq7NplDUiwT8nbRuWW-kVnAKEFIrnD0KjI9KmAbdIbxCPu25S_F).
Regarding claims 7-10, Wolff et al. teaches the claimed steps in claim 7 as follows:
(a): Wolff et al. teaches culture a MDCK cells in a disposable or single-use bioreactors ([0113] and [0018]), which also teaches claim 8.
(b): Wolff et al. teaches that after the cells reach confluence, they are washed with PBS, trypsinized and applied as an inoculum ((2-3) x10^5 cells/ml) for a 5l bioreactor containing the same media (See e.g., [0077]), where the methods according to the present invention are useful when said methods are performed in disposable or single-use bioreactors (SUB) and in stainless steel bioreactors since the surfactant can be added directly into the bioreactors allowing solubilization of the membranes of the host cells infected with the virus as well as of virus particles attached to the host cells and present in the supernatant (See [0018]). Here the description indicates the bioreactor used can be a SUB as claimed.
As for the claimed centrifuge being operated at 8,000 rpm to 20,000 rpm in claim 7 (b), it is a common knowledge that the speed of the centrifuge is depended on the centrifuge types. Nevertheless, Wolff teaches the centrifuge speed based on their need and the centrifuge type by stating that ultrafiltration may be conducted by known methods including cross flow filtration and diafiltration with molecular weight cut offs ranging from 5000 to 50,000 Da (See [0035]) and the mixture is centrifugated for 10 min with 9000g (See [0080]).
It is a common knowledge that subculturing adherent cell is generally involved in cell trypsinization, centrifuging and resuspend cells in a fresh medium based on needs. This can be evidenced by BiteSize Bio. BiteSize Bio teaches that the subculture of adherent cells requires trypsinization (See Table 1, page 2), and the old media can be removed by centrifuging at 150 x g for 5 minutes (See page 5, paragraph 3), where the 150g concentration speed is considered a low-speed centrifuge in the art. BiteSize Bio also teaches that it’s not necessary to actually remove all of the old media for suspension cells as is done for adherent cells. Instead, some of the old culture can be removed, and the remaining culture can be diluted to an appropriate cell density with fresh media (See page 5, paragraph 1), which indicates that the portion of new or old medium can be adjusted based on the needs and can be optimized to 50% to 80% of the entire culture solution through routine experimental optimization. The BiteSize Bio also teaches that if cells have reached a high density and the media has become acidic, you may wish to remove the old media by adding a centrifugation step (See page 4).
Although both Wolff and BiteSize Bio do not explicitly point out using a continuous centrifuge, a continuous centrifuge is a common piece of equipment in the art to be used in large-scale cell subculture and high-density cell, particularly for the cell harvesting and clarification stages. This can be evidenced by Sullivan’s study. Sullivan et al. teaches that using a single-use continuous discharge centrifuge to clarify high cell-density cell cultures from single-use vessels can significantly improve process times, increase yield and lower the economics of the process (See page 2, paragraph 2), and discloses that the single-use continuous discharge centrifuges use a combination of rotation and gravity to separate solids from the liquid. A feed suspension is pumped into the centrifuge where centrifugal forces push denser particle to the outside of the bowl and less dense liquids are pushed to the center. The design of the centrifuge bowl facilitates separation by using a series of conical plates, known as a disc stack, to move the clarified liquid to center and the solids to the periphery of the bowl where it is eventually discharged by the system (See page 2, paragraph 2, and Figure 1 below). Here the descriptions
PNG
media_image1.png
457
466
media_image1.png
Greyscale
teach the claimed continuous centrifuge in claims 7 and 9.
For claim 7 (c) and (d): Wolff et al. teaches the MDCK cells are infected with Influenza A PuertoRico/8/34, H1N1 (NIBSC #99-716) and are suitable for propagating the virus (See [0077]), which indicates that the influenza virus is replicated and isolated in MDCK cells.
Regarding claim 10, Wolff teaches that the present invention presents a modified downstream process of cell culture virus particles allowing a significant increase in
the production of isolated viral membrane proteins (See [0010]), where the viral membrane proteins may be separated from the remaining cell debris, microcarriers etc. by suitable filtration methods, e.g. ultrafiltration (See [0032]).
(New Rejection-necessitated by amendment) Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Wolff et al. (EP1982727A1, published on Oct. 22, 2008) as evidenced by BiteSize Bio (https://bitesizebio.com/13680/how-to-passage-cells/#:~:text=If%20you%20are%20splitting%20cells,3), and Sullivan et al. (Proanalytics, Posted on October 21, 2024 by David Koechlein, https://pro-analytics.net/continuous-centrifuge-prevent-high-density-cell-culture-fouling-optura-spy/?srsltid=AfmBOoq7NplDUiwT8nbRuWW-kVnAKEFIrnD0KjI9KmAbdIbxCPu25S_F as applied to claims 7-10 above, and further in view of Fischer et al. (Vaccine. 2018 May 24;36(22):3153-3160).
Regarding claim 11, Wolff et al. teaches the sampled influenza virus is obtained by growing and isolating the influenza virus from a cell culture, but Wolff et al. does not explicitly point out that the influenza virus isolation is based on determining the hemagglutination assay.
Fischer et al. describes the purification of cell culture-derived influenza A virus via continuous anion exchange chromatography on monoliths and the virus yield is measured by hemagglutination assay (HA assay) (See Abstract). Fischer et al. teaches that all collected fractions were analyzed by offline HA assay to estimate yields (See page 3154, right column, paragraphs 2-4) and the material balances of the chromatography runs are based on the analysis and calculations of the individual runs
to take into account the relatively high variance of the HA assay (See page 3155, right column, paragraph 1). Fischer et al. also discloses that loading four different influenza strains and, based on the HA assay, eluted 50–100% of the loaded virus with 0.5 M NaCl., and while the light scattering and UV signal increased during both steps, offline HA assay results show that the majority of the bound IAV was eluted in the first step (See page 3155, right column, paragraphs 2-3). Here the description indicates that the determining purification condition is based on a HA assay.
As for the new limitation “wherein the different conditions include one or more selected from the group consisting of buffer type, buffer concentration, pH, and conductivity” in claim 11, Wolff teaches different buffers and pH such as phosphate buffered saline (PBS) (See [0077]), Euonymus europaeus lectin (EEL) column
loading buffer (150mM NaCl, 50 mM Tris, 0.1 mM MnCl2 and 0.1mM CaCl2, pH 7.4) (See [0080]) and the membrane unit is equilibrated with 20 ml of coupling buffer (1 M
potassium phosphate buffer pH 8 (See [0087]). At the same time, Fischer teaches that conductivity can be used to monitored online to trace salt concentration/ionic strength, proteins, DNA, and IAV particles, respectively (See page 3154, bridging left column and right column).
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 Wolff, BiteSize Bio, Sullivan and Fischer to arrive at an invention as claimed. Based on the application of Fischer’s HA assay being used successfully in the influenza virus purification, one of skill in the art would have been motivated to use hemagglutination assay to determine a purification condition for the influenza virus isolation as claimed. There would be a reasonable expectation of success to develop such a method for isolating the influenza virus from the culture as claimed.
Allowable Subject Matter
The [Equation 1] CTAB treatment concentration= [{(a*TPQV(μg/mL))/(b μg/mL)}/c]*d as claimed in claim 35 is free of prior art.
Responses to Applicant’s Remarks
Applicant’s arguments filed on Mar. 10, 2026 has been received and fully considered as follows:
Applicant’s argument regarding the claim objection is considered. The objection is withdrawn.
Applicant’s argument and amendment regarding the rejections under 35 USC §112 (b) is considered. The rejections are withdrawn.
Applicant’s amendment regarding the rejection under 35 USC §112 (a) is considered. The rejection is withdrawn.
Applicant’s argument and amendment regarding the rejection under 35 U.S. C §101 is considered. The rejection is withdrawn.
Applicant’s argument regarding the rejection under 35 USC §103 regarding Phelan is considered. The rejections under Phelan are withdrawn. The argument regarding Phelan is moot.
Applicant’s argument and amendment regarding the rejections under 35 USC §103 for Wolff are not found persuasive as follows;
1). Applicant argued that Wolff discloses the use of CTAB but does not disclose or suggest at all the process concept of regularly calculating and controlling the CTAB concentration in linkage with TPQV (See Remarks, page 19).
The argument is not persuasive.
Based on the description above, Wolff teaches using the CTAB and also discloses a method to detect and calculate of the Total protein by UV-absorption
at 280 nm. At the same time, Wolff teaches that the method is based on treating influenza virions in an aqueous medium with a cationic detergent to selectively solubilize components, and separating the resulting solubilized components
from residual sub-viral particles. It is a common knowledge in the art that the amount of the detergent used is depend on the sample type and sample amount. Thus, the claimed determining CTAB treatment concentration linked with the TPQV would have been obvious unless there is evidence showing that they produce unexpected results. In addition, the instant claim does not have limitation on the process concept.
2). Applicant argued the teachings of BiteSize Bio and Fischer (See Remarks, page 19).
Applicant’s argument is not persuasive.
Wolff in view of BiteSize Bio is for teaching the specific limitation in claims 7-10 for the continuous centrifuge and how to withdraw the medium portions. Wolff in view of Fischer is for teaching the hemagglutination assay. It is applicable to use Wolff, BiteSize Bio and Fischer as a combination teaching in the office action.
3). Applicant argued that the present method measures the TPQV (total protein quantification value) of the virus sample, selects from a predefined set of reference values (b = 100 to 900) the one minimizing the absolute difference with TPQV, uses it to regularly calculate the CTAB treatment concentration, and adopts a standardized process control logic of actually performing CTAB treatment and separation at the calculated concentration.
Applicant’s argument is not persuasive.
Applicant allegedly uses a TPQV concentration to determine another concentration such as CTAB treatment concentration. According to the 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.”). Since Wolff et al. teaches a modified detergent concentrations for purifying the viral surface protein, one of ordinary skills would be able to test for an optimal concentration for the claimed CTAB concentration based on the sample amount obtained by total protein calculation through routine experimentation. Therefore, the claimed determining CTAB treatment concentration through a TPQV concentration would have been obvious unless there is evidence showing that they produce unexpected results.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas J. Visone can be reached on (571) 270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/RUIXUE WANG/Examiner, Art Unit 1672
/NICOLE KINSEY WHITE/Primary Examiner, Art Unit 1672
Prosecution Insights