DETAILED CORRESPONDENCE
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-16 are pending.
Applicant’s preliminary amendment to the claims filed 05/14/2024 is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Election
Applicant’s election without traverse of:
Group I, claims 1-15, drawn to the technical feature of a method for detecting the presence of a bacterial and/or fungal cell in a sample comprising detecting the presence of nicotinamidase activity or nicotinamidase, wherein the presence of nicotinamidase activity or nicotinamidase indicates the presence of a bacterial and/or fungal cell in the sample; the technical feature of a method for assessing the sterility of a sample comprising detecting the presence of nicotinamidase activity or nicotinamidase in the sample, wherein the lack of nicotinamidase activity or nicotinamidase as compared to a reference indicates that the sample is sterile, sterilized or free from bacterial and/or fungal cell contamination; and the technical feature of a method for monitoring bacterial and/or fungal cell contamination in a cell or tissue culture, comprising detecting the presence of nicotinamidase activity or nicotinamidase in the cell or tissue culture, wherein the presence of nicotinamidase activity or nicotinamidase indicates bacterial and/or fungal cell contamination in the cell or tissue culture.
in the reply filed 01/24/2026 is acknowledged.
Claim 16 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/24/2026.
Claims 1-15 are being examined on the merits.
Priority
The instant application is a national stage filing under 35 U.S.C. 371 of international application PCT/SG2022/050227 filed 04/18/2022, which claims foreign priority to Singaporean Application No. 10202104519X filed 04/30/2021.
Information Disclosure Statement
The Information Disclosure Statements (IDSs) submitted on 10/26/2023 and 04/16/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDSs have been considered by the examiner.
Objections to Specification
The disclosure is objected to because of the following informalities.
The use of the terms BECTON DICKINSON, BACT/ALERT, BIOMERIEUX, IMMUNOCULT, SIGMA-ALDRICH, BIOCHROM, IFUNNEL, AGILENT, ACQUITY, MASSHUNTER, GIBCO, and CARY 60, which are trade names or marks used in commerce, have been noted in this application in pages 1, 12-14, and 16. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is required.
Objections to Drawings
The drawings are objected to under 37 CFR 1.83(a) because they fail to show the colors blue, green and red in Figure 3 as described in the specification. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d).
Additionally, the drawings are objected to because Figure 15 contains 2 panels labeled only as Figure 15 with no further distinction. Each panel must be distinctly labeled, for example: Figure 15A and Figure 15B. Such labels additionally must correspond to the drawing descriptions disclosed in the specification.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action.
The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 9 is objected to for the phrase “wherein the bacterial and/or fungal cell is one that possess the PncA gene”. In the interest of improving claim form, Applicant should consider an amendment to recite “wherein the bacterial and/or fungal cell comprises a PncA gene”.
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.
Claims 2-6, 9, 11 and 13-15 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claims 2 (claims 3-5 dependent therefrom), 13 and 14 (claim 15 dependent therefrom) are indefinite for the recitation of “a reference”, as it is unclear from the claims and the specification as to the reference ration level for comparison that is indicative of the presence of a bacterial and/or fungal cell in the sample.
Claim 6 recites the limitation “the nicotinamidase gene or gene expression product” in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 9 recites the limitation “the PncA gene” in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 11 recites “the reference” in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 3 is rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 3 recites “the method of claim 2, wherein an increase in the ratio of nicotinic acid level to nicotinamide level as compared to a reference indicates the presence of a bacterial and/or fungal cell in the sample”, while Claim 2 recites “wherein an increase in the ratio of nicotinic acid to nicotinamide levels as compared to a reference indicates the presence of a bacterial and/or fungal cell in the sample”. Therefore claim 3 does not further limit claim 2 from which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-5, 8 and 11-13 are rejected 35 U.S.C. 103 as being unpatentable over Oishi et al. (J Chromatog B, 1998, 720:59; cited on the IDS filed 10/26/2023; herein referred to as Oishi98).
Claim 1 is drawn to a method for detecting the presence of a bacterial and/or fungal cell in a sample, the method comprising
detecting the presence of nicotinamidase activity or nicotinamidase,
wherein the presence of nicotinamidase activity or nicotinamidase indicates the presence of a bacterial and/or fungal cell in the sample.
Oishi98 relates to assays of nicotinamide deaminase [title].
Regarding claim 1, Oishi98 discloses an assay of nicotinamide deamidase activity using high-performance liquid chromatography [title], wherein nicotinamide deamidase is understood to be an alternate name of the enzyme nicotinamidase that catalyzes deamidation of nicotinamide (NAA) to nicotinic acid (NA) [p 59, col 1, paragraph 1], and increases of NA attributed to nicotinamidase activity correspond to the presence of bacteria [p 59, col 1, final paragraph to col 2, 1st paragraph]. Therefore Oishi98 indicates the connection between increase NA:NAA levels in a sample to nicotinamidase activity from a bacteria.
In view of Oishi98, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to determine the presence of a bacteria in a sample by detecting the presence of nicotinamidase. One of ordinary skill in the art would have been motivated to determine the presence of a bacteria in a sample by detecting the presence of nicotinamidase because Oishi98 discloses increased amounts of NA in a sample can correspond to nicotinamidase activity due to the presence of bacteria in the sample. One of ordinary skill in the art would have had a reasonable expectation of success because of the express teachings of Oishi98.
Regarding claims 2-3, Oishi98 discloses the determination of NA and NAA levels from meat-derived samples [Figure 2], wherein the detection of increased NA from meat attributed to bacterial nicotinamidase activity [p 59, col 1, final paragraph to col 2, 1st paragraph]. As Oishi98 discloses that while NA and NAA are used to process foodstuffs, they are prohibited to be added to meat in Japan, and NA is usually absent in meat while NAA is present [p 59, col 1, para 2], which is considered to correspond to a ratio of NA:NAA in a reference sample. As the disclosure of the detection of increased NA from meat attributed to bacterial nicotinamidase activity is considered to correspond to an increase in the NA:NAA ratio compared to said reference, the disclosure of Oishi98 is considered to correspond to “an increase in the ratio of NA to NAA as compared to a reference indicates the presence of a bacterial and/or fungal cell in the sample” as recited in the claim.
Regarding claim 4, Oishi98 discloses the isolation of strains isolated from meat which possessed nicotinamide deamidation activity [p 60, col 1, para 3], which is considered to correspond to “the presence of live bacterial and/or fungal cells in the sample” as recited in the claim. Regarding claim 5, Oishi98 discloses the detection of NA and NAA via HPLC focusing on the absorption over time at 261 nm [Figure 1], which is considered to correspond to UV spectroscopy.
Regarding claim 8, Oishi98 discloses an assay of nicotinamide deamidase activity using high-performance liquid chromatography [title], wherein nicotinamide deamidase is understood to be an alternate name of the enzyme nicotinamidase that catalyzes deamidation of nicotinamide (NAA) to nicotinic acid (NA) [p 59, col 1, paragraph 1], and increases of NAA attributed to nicotinamidase activity correspond to the presence of bacteria [p 59, col 1, final paragraph to col 2, 1st paragraph]. Therefore the disclosure of Oishi98 is considered to correspond to the detection of a bacterial and/or fungal cell that comprises or expresses a nicotinamidase enzyme.
Regarding claim 11, Oishi98 discloses the detection of NA and NAA in meat samples from which bacteria are isolated, wherein the corresponding reference for comparison is meat known to lack NA as discussed in the rejections of claims 1 and 4 above. As the comparison of the NA:NAA levels of the sample to the corresponding reference identified the sample as having potential bacterial presence and subsequently resulted in the isolation of live bacteria from the sample, the corresponding reference is considered to not have bacterial and/or fungal contamination as recited in the claim.
Regarding claim 12, as stated in the rejection of claim 12 under 35 USC 112(d) above, the instant specification does not specifically define contamination relevant to the number of detected bacterial and/or fungal cells, and therefore the plain definition of contamination is being used that corresponds to the presence of an impurity in a substance. In view of this interpretation, the disclosure of Oishi98 of the detection of bacterial and/or fungal cells from a sample with increased NA:NAA ratios as discussed in the rejection of claim 1 is considered to correspond to the detection of bacterial and/or fungal contamination in said sample, as Oishi98 additionally discloses that NA is not normally present in meats if not supplemented with a food additive, and therefore indicates that the bacteria responsible for generating the NA would be an impurity in the meat.
Regarding claim 13, Oishi98 discloses the method of detection nicotinamidase activity as described in rejection of claim 1 above that corresponds to the detection of the presence of bacterial and/or fungal contamination of a sample as described in the rejection of claim 12. As Oishi98 discloses the presence of the increased ratios of NA:NAA in the sample are not expected given the corresponding reference of meat only naturally contains NAA as discussed in the rejection of claim 1, the method of Oishi98 is considered to correspond to the detection of nicotinamidase activity, wherein the lack of nicotinamidase activity, corresponding to the known amounts of NA:NAA in the corresponding reference, indicates a sample is free from bacterial and/or fungal cell contamination. Put another way, as Oishi98 discloses the increased ratio of NA:NAA in comparison to a corresponding reference is associated with bacterial and/or fungal contamination of a sample, Oishi98 therefore implicitly discloses that a sample with the NA:NAA ratio similar to the corresponding reference would therefore be free of bacterial and/or fungal cell contamination.
Therefore, the invention of claims 1-5, 8 and 11-13 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claims 6-7 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Oishi98 as applied to claims 1-5, 8 and 11-13, and further in view of Ramadan et al. (Global Veteranaria, 2012, 9:648; cited on the attached Form PTO-892; herein referred to as Ramadan).
Claim 6 is drawn to the method of claim 1, wherein detecting nicotinamidase comprises detecting the nicotinamidase gene or gene expression product,
wherein the presence of nicotinamidase gene or gene expression product indicates the presence of a bacterial and/or fungal cell in the sample.
The teachings of Oishi98 as applied to claims 1-5, 8 and 11-13 are discussed above. Oishi98 does not teach detecting the nicotinamidase gene or gene expression product.
Ramadan relates to the detection of Mycobacterium bovis and Mycobacterium tuberculosis from clinical samples [title], and discusses that determination of the presence of organisms in a sample via culturing has the disadvantage that may take 6-8 weeks and require viable organisms, wherein PCR amplification of DNA is a rapid and reliable method for rapid diagnosis of the presence of a target microorganism [p 648, col 2, para 1].
Regarding claims 6-7 and 9, Ramadan teaches the use of PCR to detect the PncA gene of M. tuberculosis [p 649, col 2, para 4] from sputum samples collected from clinically diagnosed patients for the identification of Mycobacterium spp. [p 649, col 1, final paragraph], wherein the PncA gene corresponds to gene encoding a nicotinamidase enzyme according to the instant specification [p 14, final paragraph].
In view of Ramadan, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to modify the method of Oishi98 by detecting the PncA gene, as taught by Ramadan, to arrive at the claimed invention. One of ordinary skill in the art would have motivated to modify the method of Oishi98 by detecting the PncA gene because Ramada teaches PCR amplification of DNA is a rapid and reliable method for rapid diagnosis of the presence of a target microorganism, and teaches a method using PCR to detect the PncA gene to identify the presence of M. tuberculosis. One of ordinary skill in the art would have had a reasonable expectation of success because Oishi98 and Ramadan relate to methods of detecting nicotinamidase in a sample.
Therefore, the invention of claims 6-7 and 9 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claim 10 and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Oishi98 in view of Ramadan as applied to claims 1-9 and 11-13 above, and further in view of Stacey et al. (Cancer Cell Culture: Methods and Protocols, 2nd Ed, Methods in Molecular Biology, 2011, 731:79; cited on the attached Form PTO-892; herein referred to as Stacey).
Claim 10 is drawn to the method of claim 1, wherein the sample is a sample from a therapeutic product. The teachings of Oishi98 and Ramadan as applied to claims 1-9 and 11-13 are discussed above. These references do not teach the sample is a sample from a therapeutic product.
Stacey relates to cell culture contamination [title], and discusses microbial contamination to be a major issue in cell culture [abstract].
Regarding claim 10, Stacey teaches Mycoplasma as a widespread cause of cell culture contamination [p 82, para 2] whose damaging effects are well known through various reviews [p 83, first paragraph], and teaches that the success rate for complete eradication of Mycoplasma is poor [p 83, para 2]. Stacey further teaches that the immediate response to the detection of a bacterial or fungal contamination should be to discard affected cultures [p 83, Section 6, first paragraph], and that detection of Mycoplasma can be achieved using a number of different methods [p 83, para 2]. As the instant specification does not provide a specific definition for “a therapeutic product”, but gives examples of therapeutic products that include a cell, gene, protein, antibody or vaccine [p 7, final paragraph], the cell culture of Stacey is considered to correspond to the limitation of “a therapeutic product”.
In view of Stacey, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to modify the combined method of Oishi98 and Ramadan by using a sample from a therapeutic product, as taught by Stacey, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of Oishi98 and Ramadan by using a sample from a therapeutic product because Stacey indicates the detection of Mycoplasma contamination in cell culture is important for the prevention of damaging effects associated with such contamination. One of ordinary skill in the art would have had a reasonable expectation of success because both Ramadan and Stacey relate to detection of Mycoplasma in samples.
Regarding claim 14, Oishi98 teaches the detection of increased ratios of NA:NAA in meat samples compared to a corresponding reference that is attributed to nicotinamidase activity corresponding to a bacterial contamination as discussed in the rejection of claim 12 above, Stacey teaches the detection of bacterial contamination in cell culture from Mycoplasma is important to prevent the damaging effects of such contamination as discussed in the rejection of claim 10 above, and Ramadan teaches the detection of Mycoplasma in samples using PCR to identify the presence of the nicotinamidase gene as discussed in the rejection of claim 6 above. Therefore, the combined method of Oishi98, Ramadan and Stacey of detecting nicotinamidase or nicotinamidase activity in a therapeutic product of a cell culture is considered to satisfy the claim 14 limitations of detecting the presence of nicotinamidase or nicotinamidase activity in a cell culture, wherein said presence indicates bacterial contamination of the cell culture.
Regarding claim 15, the instant specification does not set forth a specific definition for “real-time”, and is therefore being examined with the plain definition of an action occurring without delay. In view of this interpretation, the combined method of Oishi98, Ramadan and Stacey of detecting nicotinamidase or nicotinamidase activity from cell cultures is considered to occur in real-time, as the detection is being carried out directly on cell cultures.
Therefore, the invention of claims 10 and 14-15 would have been obvious to one of ordinary skill in the art before the effective filing date.
Conclusion
Status of the Application:
Claims 1-16 are pending.
Claim 16 is withdrawn.
Claims 1-15 are rejected.
No claim is in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH SPANGLER whose telephone number is (571)270-0314. The examiner can normally be reached M-F 7:30 am - 4:30 pm.
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/JOSEPH R SPANGLER/
Examiner
Art Unit 1656
/David Steadman/ Primary Examiner, Art Unit 1656