DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Election/Restrictions
Applicant’s election without traverse of Group III (e.g. claims 5-13) in the reply filed on October 23, 2025 is acknowledged.
Claims 1-4 and 14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on October 23, 2025.
Claim Status
The claim set filed October 23, 2025 has been entered. Claims 1-4 and 14 are withdrawn from further consideration as being drawn to nonelected inventions as discussed in greater detail in the Elections/Restrictions section above. Thus, claims 5-13 as amended are examined on the merits herein.
Claim Objections
Claims 5 and 7-8 are objected to because of the following informalities:
(I) Claim 5, line 3 recites “functional MCM complex formed from its subunits” which is the first recitation of this limitation with the claim and therefore is missing the article “a” immediately before the word “functional” as discussed above. Thus, to promote clarity the Examiner suggests adding the article “a” as discussed above.
(II) Claim 5, line 4 recites “a functional MCM complex from MCM subunits” which the Examiner respectfully notes is the second recitation of this limitation within claim 5 as evidenced by line 3 as discussed above. Thus, to promote clarity the Examiner suggests replacing the article “a” above with the word “the” and inserting the word “its” before the phrase “MCM subunits” as discussed above.
(III) Claim 7, line 2 recites parentheses enclosing the word “immunostaining”, implying that this word is not necessarily needed in the claim. The Examiner suggests that these parentheses be removed.
(IV) Claim 8, line 2, recites “said cells has been transfected” which recites the word “has” the singular form when referring to “said cells” which is plural and therefore is grammatically incorrect. Thus, to promote clarity the Examiner suggests replacing the word “has” with the word “have” as discussed above.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 11 is rejected under 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.
Regarding claim 11, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Claim 11 recites the phrase “such as” when referring to measuring the enzymatic functions of ATPase and/or helicase of MCM proteins.
In the interest of compact prosecution, the Examiner will interpret the phrase “such as” to mean “of”, thus resulting in claim 11 being interpreted as “wherein step (b) is performed by measuring the enzymatic functions of ATPase and/or helicase activities of MCM proteins.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 pre-AIA 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
(I) Claim 5-11 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Iwami et al. (Published 30 April 2004, JP-2004131435-A, English Machine Translation, PTO-892) in view of Cheenpracha et. al. (Published August 2004, Chemical and Pharmaceutical Bulletin, Vol. 52, No. 8, pp. 1023-1025, PTO-892) and Ishimi et al. (Published 03 April 1998, Journal of Biological Chemistry, Vol. 273, Issue 14, pp. 8369-8375, PTO-892).
Regarding claims 5-11, Iwami teaches a method for screening (e.g. the method of screening, required in claim 5, line 1) a substance having the ability to specifically change the gene expression level or protein amount of Mcm2 to Mcm7 in cancer cells (e.g. the population of cells, required in claim 5, line 3), for example an anticancer agent containing the substance as an active ingredient (e.g. the anticancer compound, required in claim 5, line 1), see pg. 2, paragraph [0001]. Iwami teaches for example, cultured cancer cells derived from human cancer tissues are preferably used (e.g. the MCM subunits required in claim 9), see pg. 4, paragraph [0014, paragraph 2.
Iwami teaches the test substance is added to a cancer cell and a non-cancer cell (e.g. contacting a candidate compound with a population of cells, required in claim 5, line 2) and the gene expression level or the protein amount of Mcm2 to Mcm7 in these cells is detected (e.g. determining an amount, required in claim 5, line 2), see pg. 3, paragraph [0010].
Iwami teaches the gene expression level or protein content of non-cancer cells is detected and the gene expression level or protein content of Mcm2-7 is not changed, and only the gene expression level or protein content of Mcm2-7 of cancer cells is changed, see pg. 4, lines 2-3.
Iwami teaches “change” means to decrease or increase the gene expression amount or the protein amount of Mcm2 to Mcm7, but the gene expression amount or the protein amount of Mcm2 to 7 in the cancer cells to which the test substance is added is increased, see pg. 5, paragraph [0023].
Iwami teaches the substance selected in this way changes the gene expression level or protein amount of Mcm2 to 7 in cancer cells, and it has an effect of acting on abnormalities in mechanisms such as DNA replication in cancer cells, see pg. 5, paragraph [0024].
Iwami teaches test substances added to these cells include for example plant extracts, and wherein the compound may be a known compound, see pg. 4, paragraph [0017].
Iwami teaches the detection and quantification of the gene expression level or protein content of Mcm2 to Mcm7 in tissue cells can be arbitrarily selected and used from commonly used methods known per se, for example a coloring method or an immunohistological staining method where the measurement can be performed using a fluorescent antibody method, wherein as a fluorescent substance used for labeling an antibody, a method for labeling a secondary antibody can be used (e.g. the indirect fluorescence process (immunostaining), required in claim 7), see pg. 7, paragraph [0036].
Iwami teaches when the immunostaining of individual cells was compared, stronger immunoreactivity was observed in large nuclei, (e.g. the nucleus, required in claim 6) in cancer cells than in cells in the basal layer of normal squamous epithelium, and the expression level of MCM protein per cell increased, see pg. 10, paragraph [0061].
Iwami teaches it was found in HeLa cells used as cancer cells where the expression of all proteins of Mcm 2 to 7 was increased as compared to Wi-38 cells used as normal cells, this was confirmed not only in total extract but also in the chromatin fraction extract (e.g. MCM proteins bound to chromatin, required in claim 10), see pg. 9, paragraph [0056].
Iwami teaches since the Mcm protein has functions as DNA helicase and ATPase screening can be performed using these activities as indices (e.g. the enzymatic functions, required in claim 11), see pg. 5, paragraph [0025].
With respect to the limitations:
(i) “a period of time” when referring to contacting the candidate compound with a population of cells, required in claim 5, lines 2-3; the Examiner reasonably interprets this limitation as a physical limitation well within the scope of the artisan as Iwami already teaches screening test compounds comprising a test substance as an active ingredient within an anticancer compound by adding said compound into cancer cells. Thus, physical limitation (a) will be met by the method of Iwami above.
(ii) “functional MCM complex formed form its subunits, wherein said anticancer compound is capable of disrupting a formation of the functional MCM complex from MCM subunits” when determining the amount of said MCM complex after contact of the candidate compound with the population of cells recited in claim 5, lines 1-2, as required claim 5, lines 2-4; the Examiner reasonably interprets this limitation as a physical limitation that is met by the method of Iwami above, as Iwami teaches the test substance is added to cancer cells where the gene expression level or the protein amount of Mcm2 to Mcm7 in these cells is detected, whereby the substance specifically changes the gene expression level or protein amount of Mcm2 to Mcm7 in cancer cells by adding said test substance to said cancer cells thus resulting in an increased amount of Mcm2 to Mcm7 protein in the cancer cells.
Therefore, the physical effect of “disrupting formation of” the functional MCM complex from MCM subunits is reasonably interpreted by the Examiner to be a functional consequence of contacting the anticancer compound with said population of cells.
Additionally, as evidenced by Ishimi, Ishimi discloses minichromosome maintenance (MCM) proteins play an essential role in eukaryotic DNA replication; where biochemical analyses have indicated that MCM2–7 proteins interact; and in extracts of mitotic human cells, a complex of approximately 600 kDa, containing all six MCM proteins, have been identified; wherein based on the molecular mass of each MCM protein, this complex is probably a hexamer containing a single molecule of the six MCM proteins, see pg. 8369, left column, paragraph 1.
Thus, the Examiner reasonably interprets that when the protein amount of MCM2 to MCM7 increases within the cancer cells of Iwami after addition of the test substance of Iwami by acting on abnormalities in mechanisms such as DNA replication, which as evidenced by Ishimi, MCM proteins are essential in DNA replication, the Examiner reasonably interprets the limitation of “disrupting the formation of the functional MCM complex from MCM subunits” is met by the method of Iwami as discussed above.
(iii) “and causing cancerous cells into an abortive S phase and normal cells substantially to arrest in G1 phase”, required in claim 5, lines 5-6; the Examiner reasonably interprets this limitation is a functional consequence of disrupting the formation of the functional MCM complex by the test substance when contacted with cancerous or normal cells respectively. Since Iwami teaches said disruption of the functional MCM complex as discussed above and teaches contacting the test substance of Iwami to both cancerous and non-cancerous cells the functional consequence as outlined within limitation (iii) above will be met by the method of Iwami as discussed above.
Although, Iwami does not teach (a) the anticancer compound, required in claim 5, line 1, is the elected species 17-β-deacetyltanghinin as required in the Restriction/Election section above; and (b) the direct fluorescence process, required in claim 8.
However, in the same filed of endeavor of screening for an anti-cancer compound, with respect to limitation (a), Cheenpracha teaches that deacetyltanghinin (compound 3), from Cerebera manghas, has cytotoxic activity, suggesting its use in the treatment of cancer, see pg. 1023, abstract and pg. 1025, Table 2.
The Examiner respectfully notes Cheenpracha does not identify compound 3 as 17-β-deacetyltanghinin, however, the Examiner further respectfully notes the compound depicted as compound 3 within the Cheenpracha reference has the same structure as the elected species, as evidenced by compound 4 in Figure 1 of the instant disclosure which identifies compound 4 within Figure 1 of the instant disclosure as 17beta-Deacetyltanghinin (DAT).
It would have been prima facie obvious to one of ordinary skill in the art at the invention’s effective filing date to have incorporated the 17-β-deacetyltanghinin of Cheenpracha as a test substance within the screening method as taught by Iwami above as within the scope of the artisan as combining prior art elements according to known methods to yield predictable results. One of ordinary skill would have been motivated to add the 17-β-deacetyltanghinin of Cheenpracha within the screening method of Iwami in order to test whether or not 17-β-deacetyltanghinin is a substance having the ability to specifically change the gene expression level or protein amount of Mcm2 to Mcm7 in cancer cells as taught by Iwami above.
One of ordinary skill in the art would have had a reasonable expectation of success of adding the 17-β-deacetyltanghinin of Cheenpracha as a test substance within the screening method as taught by Iwami above; as Cheenpracha teaches compound 3, identified as 17-β-deacetyltanghinin as evidenced by the instant disclosure above, has cytotoxic activity against a variety of cancer cell lines as discussed in Table 2 of Cheenpracha above; additionally Iwami teaches the test substance may be from plant extracts and may be a known compound as discussed above.
With respect to limitation (b) and within the same field of endeavor of fluorescence processes, Ishimi teaches native forms and truncated forms of the mouse MCM2 gene were cloned in pEGFP-N1 (e.g. the plasmid, required in claim 8, line 1) at the HindIII sites to synthesize MCM2-GFP fusion proteins where the carboxyl-terminal ends of the MCM2 proteins were fused to the amino-terminal end of GFP (green fluorescent protein) (e.g. the one or more MCM subunits fused with a fluorescent protein, required in claim 8, line 3); where the cloned DNAs were transfected into HeLa cells using Tfx 20 (Promega) (e.g. the direct fluorescence process, required in claim 8), see pg. 8370, left column, paragraph 2.
The Examiner respectfully notes with particular respect to the limitation “the location of said fluorescently labeled MCM subunits is then detected after said cells have been treated with said candidate compound for a certain duration”, required in claim 8, lines 3-5; the Examiner reasonably interprets this limitation as a physical limitation as Iwami teaches when the immunostaining of individual cells was compared, where stronger immunoreactivity was observed in large nuclei in cancer cells than in cells in the basal layer of normal squamous epithelium, and the expression level of Mcm protein per cell increased. Thus, the Examiner reasonably interprets the physical limitation discussed above is met by the method of Iwami discussed above.
It would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have incorporated limitations (a)-(b) within the screening method as taught by Iwami above as within the scope of the artisan as combining prior art elements according to known methods to yield predictable results. One of ordinary skill would have been motivated to (a) add the 17-β-deacetyltanghinin of Cheenpracha within the screening method of Iwami in order to test whether or not 17-β-deacetyltanghinin is a substance having the ability to specifically change the gene expression level or protein amount of Mcm2 to Mcm7 in cancer cells as taught by Iwami above and (b) to use the fluorescence method of Ishimi as an immunohistological staining method where the measurement can be performed using a fluorescent substance as taught by Iwami as discussed above.
One of ordinary skill in the art would have had a reasonable expectation of success of incorporating limitations (a)-(b) within the screening method as taught by Iwami above; as (a) Cheenpracha teaches compound 3, identified as 17-β-deacetyltanghinin as evidenced by the instant disclosure above, has cytotoxic activity against a variety of cancer cell lines as discussed in Table 2 of Cheenpracha above; additionally Iwami teaches the test substance may be from plant extracts and may be a known compound as discussed above; and (b) Iwami teaches the detection and quantification of the gene expression level or protein content of Mcm2 to Mcm7 in tissue cells can be arbitrarily selected and used from commonly used methods known per se, for example a coloring method or an immunohistological staining method as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
(II) Claims 12-13 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Iwami et al. (Published 30 April 2004, JP-2004131435-A, English Machine Translation, PTO-892), Cheenpracha et. al. (Published August 2004, Chemical and Pharmaceutical Bulletin, Vol. 52, No. 8, pp. 1023-1025, PTO-892) and Ishimi et al. (Published 03 April 1998, Journal of Biological Chemistry, Vol. 273, Issue 14, pp. 8369-8375, PTO-892) as applied to claims 5-11 above, and further in view of Lau et al. (Published 26 July 2010, Oncogene, Vol. 29, pp. 5475-5489, PTO-892).
Iwami, Cheenpracha and Ishimi address claims 5-11 as written above. Although, Iwami, Cheenpracha and Ishimi do not teach the conformation step performed using flow cytometry, required in claims 12-13.
However, in the same filed of endeavor of detecting and quantifying Mcm proteins, Lau exemplifies small interfering RNA (siRNA) knockdown of MCM2, MCM3 and MCM7 inhibited medulloblastoma (MB), where flow cytometry data indicated that knockdowns of MCM2 or MCM7 in DAOY cells further increased the arrests and eventually induced prominent apoptosis after 48 h, see pg. 5479, right column, paragraph 1. Lau teaches flow cytometric histograms of propidium iodide-stained MB cells, treated with transfection reagents alone or with MCM2 siRNA, MCM3 siRNA or MCM7 siRNA, pp. 5483-5484, Figure 4b.
It would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have incorporated flow cytometry as taught by Lau into the detection and quantification of the gene expression level or protein content of Mcm2 to Mcm7 in tissue cells as taught by Iwami above as within the scope of the artisan as combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to incorporate the flow cytometry of Lau into the method of Iwami above in order to detect and quantify the amount of Mcm2 or Mcm7 protein within the cancer cells of Iwami after screening the test compound as taught by Iwami above.
One of ordinary skill in the art would have had a reasonable expectation of success to incorporate the flow cytometry of Lau into the method of Iwami above, as Iwami teaches the detection and quantification of the gene expression level or protein content of Mcm2 to Mcm7 in tissue cells can be arbitrarily selected and used from commonly used methods known per se, for example as a coloring method; and wherein Lau teaches flow cytometry was conducted using propidium iodide as a fluorescent dye as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
Conclusion
No claims are allowed in this action.
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/JARET J CREWS/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691