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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 April 22, 2026 has been entered.
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on April 22, 2026. Claims 1-4, 6-10, 14-20 and 25 are pending and currently examined.
Claim Objections
(Previous objection- withdrawn) Claim 1 is objected to because of the following informalities:
The “each aliquot with an aqueous volume of 10 ml or less” should be “wherein each aliquot with an aqueous volume of 10 ml or less”.
This objection is withdrawn in view of the amendment filed on April 22, 2026.
(New) Claim 25 is objected to because of the following informalities:
The “comprising” in claim 25 should be “comprises”.
Appropriate correction is required.
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(Previous rejection- withdrawn) Claims 1-4, 6-10 and 14-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly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This rejection is withdrawn in view of the amendment filed on April 22, 2026.
(New) Claims 20 and 25 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.
Claims 20 and 25 recite a phrase “…the nucleic acid sequence according to SEQ ID NO: 1”, where the “according to” renders the claims indefinite. It is unclear if the “according to” means “consisting of “or “comprising”.
Accordingly, one of ordinary skill in the art will not know the metes and bounds of the claims.
Claim 20 recites the limitation “the nucleic acid sequence” in reference to claim 1. There is insufficient antecedent basis for this limitation in the claim.
(New) Claims 1-4, 6-10 and 14-20 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 b) recites that “the aliquots are passaged using a dilution factor of at least 2 at each passage” that means that the total volume will enlarge or increase in order to make the dilution. Therefore, the base claim 1 omitted the steps on how to make the “combined aqueous volume of the plurality of individual cell culture aliquots is reduced by at least 50% between the start and end of step b)”.
The base claim 1 c) recites that “testing a test sample from the cell culture aliquots at the end of step b) for the presence of replication competent virus”, however, it does not specify how to test a test sample. Therefore, the base claim 1 omitted the steps on how to test the “replication competent virus”.
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.
(New) Claims 1-4, 6-10 and 14-19 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 detecting HIV replication competent virus in HEK293T and C8166-45 cells using F-PERT (Fluorescence Product-Enhanced Reverse Transcriptase) assay, does not reasonably provide enablement for using a method being enabling to detect any replication competent virus in any cell culture through any testing method.
The amended base claim 1 is directed to a method for detecting replication competent virus in cell culture aliquots, the method comprising a) culturing a plurality of individual cell culture aliquots comprising virus-permissive cells and (i) a gene therapy product or (ii) end of production cells wherein each aliquot has an aqueous volume of 10 ml or less; b) culturing the aliquots wherein the aliquots are passaged using a dilution factor of at least 2 at each passage. wherein the combined aqueous volume of the plurality of individual cell culture aliquots is reduced by at least 50% between the start and end of step b); and c) testing a test sample from the cell culture aliquots at the end of step b) for the presence of replication competent virus, wherein the method is performed before clinical release of the gene therapy product.
Based on the claims, the claimed method requires a generic replication competent virus, a generic virus-permissive cells and a generic testing assay. However, the instant specification discloses that the replication competent virus is a mutant HIV virus (See e.g., [0294]) and the cells are C8166-45 cell line and HEK293 cell line, and the testing method is F-PERT qPCR (See e.g., [0279] to [0281]). Thus, the instant specification does not provide examples to support the claimed method to use any virus-permissive cell lines with any virus through any method for detecting the replication competent virus. Accordingly, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wriqht, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).1
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Id. While it is not essential that every factor be examined in detail, those factors deemed most relevant should be considered.
In the instant invention, the disclosure fails to provide adequate guidance pertaining to a number of these considerations as listed above:
Nature of the invention/Breadth of the claims. The instant claim 1 is drawn to a method for detecting replication competent virus in cell culture aliquots, where the method comprises a generic replication competent virus, a generic cell line to grow a generic virus and a generic test to detect the replication competent virus.
State of the prior art/Predictability of the art. The concept of detecting replication competent virus in a cell culture is known in the art as Sastry taught at: “Although vectors are designed to be replication defective, recombination events during vector production could lead to the generation of replication competent retroviruses (RCR) or replication competent lentiviruses (RCL). Careful screening of vector prior to human use must ensure that patients are not inadvertently exposed to RCR or RCL. We describe methods capable of detecting low levels of virus contamination and discuss the current regulatory guidelines for screening gene therapy products intended for human use” (See Abstract). At the same time, Sastry teaches a comparable method for the detection of replication competent retrovirus and lentivirus.
The level of one of ordinary skill/The existence of working examples. the instant examples 1-2 only disclose Wt HIV, HIV LiA3Vif+ and HIV LiA4 cultured in C8 l 66 cell line with a detection method F-PERT qPCR. Accordingly, the invention does not provide sufficient evidence showing that any type of replication competent virus, any virus-permissive cells and any testing assay are used the claimed method.
The amount of direction provided by the inventor/ The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Based on the description above, the specification only discloses a method for detecting a specific replication competent virus with a specific cell line through a specific detection assay. However, the instant base claim 1 is directed to a method for detecting any replication competent virus in any cell culture with any testing method.
M.P.E.P. §2164.03 [R-2] states: [I]n applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In re Soil, 97 F.2d 623,624, 38 USPQ 189, 191 (CCPA 1938). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833,839, 166 USPQ 18, 24 (CCPA 1970). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488,496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Based on the descriptions above, the specification does not provide sufficient guidance to allow one skilled in the art to practice the claimed invention on the full scope with a reasonable expectation of success and without undue experimentation. In the absence of such guidance and evidence of working examples, the specification fails to provide an enabling disclosure commensurate in scope with the claim.
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) Claims 1-4, 6-10 and 14-16 and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Sastry et al. (Methods Mol Biol. 2009;506:243-63, hereinafter “Sastry”).
The amended base claim 1 is directed to a method for detecting replication competent virus in cell culture aliquots, the method comprising:
a) culturing for at least nine days a plurality of individual cell culture aliquots comprising virus-permissive cells and (i) a gene therapy product or (ii) end of production cells that were used to manufacture the gene therapy product, wherein each aliquot has an aqueous volume of 10 ml or less;
b) culturing the aliquots for at least a further six days, wherein the aliquots are passaged using a dilution factor of at least 2 at each passage,
wherein the combined aqueous volume of the plurality of individual cell culture aliquots is reduced by at least 50% between the start and end of step b); and
c) testing a test sample from the cell culture aliquots at the end of step b) for the presence of replication competent virus,
wherein the method is performed before clinical release of the gene therapy product.
Sastry teaches a method for detecting replication competent retrovirus (RCR) and Lentivirus (RCL) and discloses a molecular and biological assay for detection of RCL associated with lentiviral vectors which is outlined in the Fig. 2 (See below). In the method chapter, Sastry further discloses that in an assay for detecting RCL associated with HIV-1 based vectors, the test article is used to inoculate a cell line (C8166-45 derived from human umbilical cord blood lymphocytes) that is permissive for infection and growth of HIV-1, and the transduced cell line is cultured for 21 days to amplify any RCL in the test article. Sastry also teaches a detailed method using the C8166 cell lines to detect RCL in HIV-1 vectors, a maxim of 12 ml medium is needed in per 75 CM2 flask or 50 ml culture tube (See page 255, 3.2.2).
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Therefore, Sastry teaches the step a) of claim 1, where the amended “at least nine days” is taught by “the transduced cell line is cultured for 21 days…”, the “virus-permissive cells” is C8166 cell line, the “(i) a gene therapy product” is indicated by “we describe methods capable of detecting low levels of virus contamination and discuss the current regulatory guidelines for screening gene therapy products intended for human use” (Abstract). As for the newly added limitation of “10 ml or less”, Sastry teaches that the cell can be seeded in the 6-well plate (See page 253) or 25-cm 2 flasks (See page 252; Table 1), where the culture volume is less than 10 ml. Also, the 6-well plate is considered as “a plurality of individual cell culture aliquots” as claimed.
For the claimed step b) in the base claim 1, Sastry teaches that after three weeks, cell free medium from amplified cells is used to infect naïve C8166 (Indicator) cells, which are cultured for an additional seven days and analyzed for the presence of viral markers (See page 247, paragraph 1), where the “seven days” here can be considered to teach the “a further six days” as claimed in step b). As for the dilution factor claimed, Sastry teaches a serial dilution at “… Flasks #2–5: 10−2, 10−4, and 10−6…” (See page 253, paragraph 3.1.3), which can be considered a dilution factor at 2. Sastry also teaches the cells should be passaged a minimum of five times during the three-week period and at least two times per week. The amplification kinetics do allow scaling down of large flasks with later passages, as demonstrated in Table 2 (See page 252, paragraph 2 and Table 2 below), which indicates the passage of the cell aliquots and the total volume can be reduced. Therefore, the “the total volume across the plurality of aliquots is reduced by at least 50%” as claimed can be achieved through experimental optimization based on the cell density and culture volume unless there is evidence showing that they produce unexpected results.
As for the amended limitation of claim 1 c), Sastry teaches that sensitive assays have been developed for detection of RCL indicative markers including the p24 gag antigen (by ELISA), viral reverse transcriptase (by product enhanced reverse transcriptase or PERT), psi-gag sequences that result from a recombination between vector and packaging constructs (by PCR) and the psuedotyping envelop VSV-G (by PCR) (See page 247, paragraph 1). Here the new added limitation of “testing a test sample from the aliquots at the end of step b)” is taught by Sastry’s teaching at culturing a further seven days and then the sample will be tested.
As for the limitation on “wherein the method is performed before clinical release of the gene therapy product”, Sastry teaches that screening of vector prior to clinical use has generally relied on biologic assays aimed at documenting a replication competent virus, rather than surrogate markers of virus (See page 245, paragraph 2).
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Thus, the invention as a whole is clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding claims 2-3, Sastry teaches their detention method is for replication competent retrovirus and Lentivirus (See Abstract).
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Regarding claims 4 and 6-10, Sastry teaches the virus-permissive cells such as Mus dunni cells can be seeded at different volume based on the Flask volume and cell density (See Table 1 and below), which includes the started volume of 11ml, 10ml, 5ml or 3ml and 115ml and the cell density between 1 x 10^5 total cells/ml to about 1 x 10^7 total cells/ml (Claim 4 & 9-10). Sastry also teaches that the virus-permissive cells can be C8166 cell that is permissive for infection and growth of HIV-1 and derived from human umbilical cord blood lymphocytes (See page 247, paragraph 1), which is a non-adherent cell line (claims 7-8). Sastry teaches a method for detecting replication competent retrovirus (RCR) using biologic assays (See Table 1, page 251 and below). It is a common knowledge in the art that the RCR is the virus particles capable of infecting cells and replicating to produce additional infectious particles (Claim 6).
Regarding claims 14-16, Sastry teaches that the plate for PCR test is 6-well plates (See e.g. page 249, paragraph 2), which teaches claims 14-15. As for the limited plates with 12-well plate or a 24-well in claim 16, one of ordinary skills would be able to use any cell culture plates based on the needs.
Regarding claims 18-19, Sastry teaches that the sensitive assays have been developed for detection of RCL indicative markers including the p24 gag antigen (by ELISA), viral reverse transcriptase (by product enhanced reverse transcriptase or PERT), psi-gag sequences that result from a recombination between vector and packaging constructs (by PCR) and the psuedotyping envelop VSV-G (by PCR) (See page 247, paragraph 247).
(Previous rejection- maintained) Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Sastry as applied to claims 1-4, 6-10 and 14-16 and 18-19 above and in view of Swiech et al. (Methods in Molecular Biology Book 2086, published on Nov. 09, 2019, hereinafter “Swiech”).
Claim 17 is directed to a method of claim 1, wherein steps a) and b) are automated.
Sastry teaches a method for detecting replication competent virus in a test sample by culturing the virus-permissive cells such as C8166 cells and a portion of the test samples, and then testing for the presence of replication competent virus. However, it is silent on an automated method.
Swiech teaches the Chimeric Antigen Receptor T Cells: Development and Production in their book Chapter, which include the production of Lentivirus for the establishment of CART-T Cells and the replication-competent retrovirus (RCR) detection (See page Vii and Viii). Swiech also teaches a new processing option for seeking automation and controlled expansion process to ensure that critical quality attributes of the cell production (See e.g. page 141, paragraph 2). Swiech teaches that automation can improve reproducibility and reduce human errors, while functionally closing this operation helps to manage contamination risks (See page 151, Introduction). Also, Swiech teaches Determine the cell density of the culture by performing a cell count using an automated cell counter (See page 79, Method 3.1), and discloses that new GMP-compliant technology for cell expansion is the CliniMACS® Prodigy (Miltenyi Biotec), which is a one-solution, automated platform, that includes all the CAR-T cell manufacturing steps: cell selection, activation, transduction, expansion, cell washing, and final formulation in a fully closed system that can reducing operator time and the cost (See e.g page 145, paragraph 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 the automated culturing system into Sastry’s research and arrive at an invention as claimed. Since the Swiech’s automated system for cell culturing is focused on the T cell culturing system, one of skill in the art would have been motivated to introduce the automated system into the C8166 cell-based RCL detection system based on the advantage described above. There would be a reasonable expectation of success to adopt the automated T cell to culturing C8166 because C8166 is derived from human umbilical cord blood lymphocytes, which is also a T cell line.
Allowable Subject Matter
The SEQ ID NO: 1 of claims 20 and 25 is free of art.
Responses to Applicant’s Remarks
Applicant’s arguments filed on April 22, 2026 has been received and fully considered.
Applicant’s amendment regarding the objection is considered. The objection is withdrawn.
Applicant’s amendment regarding the rejections under 35 U.S.C. § 112 (b) is considered. The rejection is withdrawn.
Applicant’s argument on rejection under 35 U.S.C. § 103 is not found persuasive as follows:
1). Applicant argued that the rejection is based on an improper reading of Sastry and an analysis that dissects the claimed method into individual elements without addressing the claimed invention as an integrated whole. When properly construed in light of the Specification, and considered as a whole, the claimed subject matter is neither taught nor suggested by Sastry, and it is clear that the Office has not established a prima facie case of obviousness (See Remarks, page 6).
Applicant’s argument is not persuasive.
The base claim 1 is directed to a method for detecting replication competent virus in cell culture aliquots, where Sastry teaches a method for the detection of replication competent retrovirus and lentivirus in a cell culture. The elements Sastry taught are proper for each limitation as claimed.
Therefore, the invention as a whole is clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
2). Applicant argued that Sastry discloses conventional flask-based amplification assays in which a test article is introduced into a culture system and maintained over time to amplify any replication competent virus. The process described in Sastry is structured around maintaining a culture within a vessel that is passaged over time to sustain cell growth and amplification. Sastry does not describe or suggest organizing the assay as a plurality of discrete cell culture aliquots that are managed collectively, nor does it describe controlling relationships between multiple parallel culture volumes (See Remarks, page 6).
Applicant’s argument is not persuasive.
Although Sastry does not explicitly use the term of “plurality”, Sastry teaches culturing the cells in many flasks and plates with different volume (See e.g., page 249, 2.1 RCR testing; Table 1 and Table 2 above), and the cell media from the amplification phase is collected (See e.g., page 245, paragraph 3). Also, the amended base claim 1 does not have limitations on “discrete cell culture aliquots” and “controlling relationships between multiple parallel culture volumes”.
3). Applicant argued that the present claims require initiating and maintaining a plurality of individual aliquots, each having a small volume (≤ 10ml), and further require that the total combined volume of those aliquots be reduced by at least 50% during the process. This is not merely a modification of Sastry' s protocol, but a fundamentally different process design (See Remarks, page 6).
Applicant’s argument is not persuasive.
Sastry teaches a small volume culturing cell with less than 10ml medium (See e.g., Table 1 above). It is a common knowledge in the art that the culturing medium volume depend on the volume of culture flask, vessel or plates, cell density, etc. Also, it is a common technology to combine volume of aliquots to certain volume based on the needs. Thus, the culturing or combine volume would have been obvious unless there is evidence showing that they produce unexpected results.
4). Applicant argued that the interpretation of "10 ml or less" is inconsistent with the specification and is based on a technical misreading of Sastry (See Remarks, page 7).
Applicant’s argument is not persuasive.
First, Sastry taches the cells can be cultured in a volume less than 10ml aliquot.
Second, the instant claims do not have the limitation “a discrete cell culture volume that is present within a single cell culture reaction chamber”.
Third, Applicant’s argument on “the volumes cited in Sastry's tables correspond to the amount of test article (i.e., the sample being tested) introduced into a culture system, not to the total volume of the resulting cell culture” (See Remarks, page 7, paragraph 4) is not persuasive because Sastry teaches that the size of the amplification phase depends on the volume of the sample being tested (See page 251, 3.1.2). It is obvious that one of skilled in the art can adjust the volume to "10 ml or less" based on the needs. In addition, the instant base claim 1 does not have limitation if the “volume of 10 ml or less” is a working volume or not.
Fourth, the argument of “Sastry does not disclose or suggest the use of total culture volumes of 10 ml or less as a general or preferred condition for viral amplification, particularly in the context of testing gene therapy products prior to clinical use” (See Remarks, page 7, paragraph 5) is also not persuasive. The volume used for cell culture depend on many factors and one of ordinary skills would be able to test for an optimal volume through routine experimentation. Therefore, the claimed volume would have been obvious unless there is evidence showing that they produce unexpected results. In addition, there is no limitation in the base claim 1 if the “10
ml or less” volume is a total volume or if it is the volume particularly in the context of
testing gene therapy products prior to clinical use.
5). Applicant argued that Sastry does not teach or suggest the claimed feature that each individual cell culture aliquot-defined as the total amount of cell culture composition within an individual reaction chamber-be 10 ml or less (See Remarks, page 8).
Applicant’s argument is not persuasive.
Based on the description above, Sastry teaches an individual cell culture can be used by disclosing add appropriate number of C8166 cells for the test article according to calculations from Table. 3 (See page 255, paragraph 1 and Table 3), which is not an implicit assumption. In addition, the instant claims do not have a limitation “configuring the assay as a plurality of discrete culture aliquots” (See Remarks, page 8, paragraph 1).
6). Applicant argued that Sastry does not teach or suggest reducing the combined culture volume of a plurality of aliquots, and does not employ a plurality of aliquots that are maintained and managed in parallel, it does not involve a "combined aqueous volume" of multiple individual aliquots, as required by the present claims. The concept of reducing the aggregate volume of multiple discrete aliquots is entirely absent from Sastry (See Remarks, bridging pages 8-9).
Applicant’s argument is not persuasive.
“Reducing the combined culture volume of a plurality of aliquots” and "combined aqueous volume" should depend on the application needs, cell culture types, manufacture’s capacity and many other factors. Sastry teaches that 5% of the final product volume must also be screened (See page 248, paragraph 3). It is obvious that one of ordinary skills would be able to test for an optimal volume through routine experimentation based on the needs.
As for the argument on “Sastry consistently emphasizes the importance of maintaining assay conditions that support sensitive detection of replication competent virus, noting that detection systems must "anticipate a currently theoretical virus" (See Remarks, page 9, paragraph 2), it is not persuasive because this does not change Sastry’s teaching on a method for detecting the Replication Competent Retrovirus and Lentivirus. In addition, the instant base clam 1 does not have limitation on “a plurality of aliquots that are maintained and managed in parallel” (See Remarks, page 8, paragraph 7).
7). Applicant argued that the Office has not identified any teaching or suggestion in Sastry of the claimed requirement that the combined aqueous volume across a plurality of individual aliquots be reduced by at least 50%, nor provided a factual basis for concluding that such a feature would arise through routine optimization (See Remarks, page 9, paragraph 4).
Applicant’s argument is not persuasive.
Based on the description above, combining aqueous volume across a plurality of individual aliquots be reduced by at least 50% is a routine technology in the art. One of ordinary skills would be able to test for an optimal culture volume through routine experimentation unless there is evidence showing that they produce unexpected results.
8). Applicant argued that one skilled in the art would have no motivation to modify Sastry in the manner suggested and no reasonable expectation of success in doing so (See Remarks, pages 9 and 10).
Applicant’s argument is not persuasive.
First, Sastry teaches culturing cells in different volume that can be multi-aliquot. Sastry teaches a plurality of individual cell culture aliquots, where each having an aqueous volume of 10 ml or less (See e.g., Table 2 above). In addition, “configuring an assay” and “managing such aliquots in a manner” are not limitations in the instant claims.
Second, Sastry teaches using different size vessel or flask or plate to culture cells that can be a plurality of small-volume aliquots. Combining culture volume across such aliquots is a routine of technology in the art. One of ordinary skills would be able to combining desired culturing volume through routine experimentation unless there is evidence showing that they produce unexpected results.
9). Applicant argued that the addition of Swiech to the rejection of claim 17 does not remedy the fundamental deficiencies of Sastry.
Applicant’s argument is not persuasive.
Sastry in view of Swiech used here is to teach a specific limitation of claim 17. It is applicable to use it as a combination teaching for the office action.
Applicant’s Declaration filed on April 22, 2026 has been received and fully considered.
However, the Declaration is not found persuasive.
1). The declaration items 1-7 allegedly provide the same argument as the Remarks for “a plurality of individual cell culture aliquots, each having a small volume of 10 ml or less, and further requires that the combined aqueous volume of these aliquots be reduced by at least 5 0% during the course of the assay”.
Based on the description above, “small volume of 10 ml or less” or the volume “reduced by at least 50%” can be achieved through experimental optimization unless there is evidence showing that they produce unexpected results. As for the item 7, the instant claims do not have the limitations on the “sensitivity”, or “a loss of viral particles and reduced amplification efficiency” in the declaration.
2). The declaration argued that “this result was surprising, and contrary to the expectations of those skilled in the art at the time of the invention”. However, applicant does not provide data or support for the surprising result.
3). In addition, the arguments in the Remarks (See Remarks, page 10, paragraphs 3-4) regarded to the declaration is not persuasive because “employing small-volume aliquots and further reducing the combined volume of the culture system during the assay” is a routine technique in the art and there is no evidence and experimental data to support the “surprising outcome”.
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
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