DETAILED ACTION
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 .
Applicants filed a Preliminary Amendment September 1, 2022, in which Applicants amended claims 1-14, canceled claims 16-17, and added new claims 18-20. Thus, claims 1-15 and 18-20 are pending in this application, and are under examination.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. 15/311,460, filed on November 15, 2016.
Information Disclosure Statement
The Information Disclosure Statement filed April 15, 2022 has been considered.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The disclosure is objected to because of the following informalities:
The SEQ ID NOS: 01-09 should be changed to SEQ ID NOS: 1-9 throughout the specification.
Throughout the specification, opening quotes should be located at the same level as closing quotes.
The Table at page 53 is not numbered.
The use of the terms TRITON® at the Table on page 54 and Table 40; POROS® at page 55, line 7; NANODROP® at page 56, line 4 and page 59, line 17; ALLPREP® at page 56, line 21; page 79, line 9; and page 88, line 7; HIGH PURE® at page 56, line 24; SYBR® at page 63, lines 5 and 8; page 89, lines 6 and 11; and page 101, lines 1 and 10; ACTIVE MOTIF® at page 65, line 23; NUPAGE® at page 66, line 19; CEDEX® at page 68, lines 2 and 15; page 69, line 10; page 71, line 5; and page 75, line 32; NUCLEOFECTOR® at page 68, line 23; page 70, line 22; and page 75, line 14; CELLAVISTA® at page 69, line 5 and page 71, line 6; AMAXA® at page 70, line 18; GENE PULSER® at page 75, lines 12 and 16; EPITECT® at page 79, line 12 and page 88, line 10; XLFIT® at page 87, line 9; LIGHTCYCLER® at page 89, lines 5, 6, and 11; page 100, line 9; and page 101, lines 2 and 10; and TAQMAN® at page 95, line 19; which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
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.
Claim Objections
Claim 13 is objected to because of the following informalities:
At claim 13, line 2, “CHO” should be changed to “Chinese Hamster Ovary (CHO).”
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.
Claims 1-15 and 18-20 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.
At claim 1, lines 5-7, it is not clear how close to the promoter the level of histone 3 acetylation should be determined. Although the claim recites that close to the promoter is within several hundred base pairs, such a wide range is deemed to be indefinite.
Claims 2-15 and 18-20 depend from claim 1, and are therefore included in this rejection.
At claim 2, line 9, it is not clear how close to the promoter the level of histone 3 acetylation should be determined.
Claim 4 recites the limitation "the first multitude of cells" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 4 recites the limitation "the second multitude of cells" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 11 recites the limitation "the second multitude of cells" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 11 recites the limitation "the first multitude of cells" in line 3. There is insufficient antecedent basis for this limitation in the claim.
Claim 12 depends from claim 11 and is therefore included in this rejection.
Claim 12 recites the limitation "the second multitude of cells" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim.
Claim 12 recites the limitation "the first multitude of cells" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim.
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 1-8, 11-15, and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Goepfert et al. (PCT Patent Application Publication No. 2011/128377, published October 20, 2011, and cited in the Information Disclosure Statement filed April 15, 2022) in view of Paredes et al. (35 Biotechnology Letters 987-993 (2013), and cited in the Information Disclosure Statement filed April 15, 20222) and Urbanucci et al. (72(11) The Prostate 1223-1232 (2012), and cited in the Information Disclosure Statement filed April 15, 2022).
Regarding claim 1, Goepfert discloses a method for selecting a cell that expresses a polypeptide over a long term based on the determination of methylation of the nucleic acid encoding the promoter, which is operably linked to a structural gene encoding the polypeptide (page 2, lines 20-35, page 3, lines 1-24, and Table on page 21). Goepfert discloses determining the methylation frequency at CpG sites at 425 of SEQ ID NO:1 (page 4, lines 5-15 and page 24, lines 8-10).
Regarding claim 2, Goepfert discloses isolating the DNA from at least 10 cells of a cultivation of a cell that has a production rate of a polypeptide that is after a cultivation time of 30 generations of the cell in the absence of selection agent less than 90% of the production rate of the cell after the first
generation of the cultivation; modifying the cytosine of the isolated DNA by bisulfide
treatment; determining the methylation frequency of the CpG site in the promoter; and selecting a
cell clone in which the methylation frequency is below 5% (page 2, lines 20-35, page 3, lines 1-24, and Table on page 21).
Regarding claims 3 and 14, Goepfert discloses that the polypeptide can be an antibody light chain (page 6, lines 1-11). Goepfert discloses that the copy number of stable integrated light chain expression cassettes can be determined by selecting a cell clone/cell line having a copy number of 10 or less (page 26, lines 21-28).
Regarding claim 6, Goepfert discloses methylation-specific real-time qPCR to allow for rapid and sensitive measurement of hCMV-MIE methylation and transgene copy numbers (page 5, lines 7-20). Goepfert discloses that the method includes isolation of DNA from the cells, performing methylation specific PCR, and determining the results of a CpG site with high methylation frequency withing the promoter nucleic acid (page 14, lines 25-30).
Regarding claims 7-8, Goepfert discloses methylation sensitive primers and insensitive primers (universal) that have the sequences of SEQ ID NO: 9 and 11 and 11 and 18 that can be used for determining the methylation frequency at CpG sites at 425 of SEQ ID NO:1 (page 4, lines 5-15).
Regarding claim 13, Goepfert discloses that the cell clone/cell line can be a Chinese Hamster Ovary (CHO) cell clone/cell line (page 5, lines 7-25 and page 7, lines 16-29).
Regarding claim 15, Goepfert discloses that antibodies can have different specificities based on different classes of antibodies, which is interpreted as including bispecific antibodies (page 6, line 1 to page 7, line 3 and Example 2).
Regarding claim 20, Goepfert discloses that the method includes providing a mammalian, non-human cell and transfecting the cell with a nucleic acid encoding the promoter operably linked to the structural gene (page 4, lines 22-30). Goepfert discloses that the promoter has the sequence of SEQ ID NO: 1 (page 4, lines 5-15).
However, Goepfert fails to disclose that the selection is based on acetylation of histone
3 (H3) and the ratio of histone 3 acetylation and the level of histone 3. Goepfert fails to disclose the location of the histone 3 acetylation in relation to the location of the promoter. Goepfert fails to explicitly disclose the use of two groups of the same type.
Paredes discloses that the gradual loss of recombinant protein expression in CHO cell lines during prolonged subculture is a common issue, which seriously affects the industrial
production processes of therapeutic proteins (abstract). Paredes discloses that loss of recombinant copies due to genetic instability of CHO cells, and epigenetic silencing of transgene sequences are main
causes of production instability (abstract).
Paredes discloses that decrease in H3 acetylation in close to transcription start site (TSS) result in instability of producing recombinant antibodies in CHO cells (page 992, first column, Figure 3 and legend). Paredes discloses that the level of H3ac at recombinant sequences seems to be important for the stability of recombinant protein expression during prolonged culture (page 992, column 1, first paragraph).
Urbanucci discloses the amount of total H3 has been used as a measure of nucleosome
density (page 1230, column 1, first paragraph). Urbanucci discloses that measuring the ratio
of AcH3 and H3 pan indicates the number of histone octamers in the regulatory regions of the
gene, whereas a higher ratio of AcH3 and H3 pan indicates a reduced number of nucleosomes in
the regulatory region, which provides a more open chromatin. Urbanucci discloses that H3 acetylation relive transcriptional repression given by nucleosomal positioning (page 1230, column 1, first paragraph).
It would have been obvious to an ordinary skilled in the art before the effective filing date of the claimed invention that when choosing a cell/clone for producing recombinant protein, stability and epigenetic silencing is among the important factors that determines the long term recombinant production based on the disclosures of Goepfert and Paredes The ordinary skilled in the art would thus be motivated to pick a clone that has 5% less methylation at position 425 of SEQ ID NO:1 as taught by Goepfert and also show higher level of acetylation of H3 as taught by Paredes because such clone
will have stability as demonstrated by Paredes. In addition, one of ordinary skill in the art would be motivated to determine acylation of histone 3 at locations in varying proximity of the transcription start site of the promoter, including within several hundred base pairs, which includes within 200 base pairs upstream of the promoter and transcription start sites, because, as disclosed by Paredes, decrease in H3 acetylation close to the start site causes instability of the cell clones/cell lines. In addition, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to determination of histone 3 acetylation several hundred bases away from the CpG methylation site at position 425 because this allows for accurate measurement of both CpG methylation and histone 3 acetylation without interference with the two analyses. Thus, one of ordinary skill in the art would be motivated to measure H3 acetylation in order to select high-producing, long-term producing cell clones/cell lines. Further, Urbanucci’s disclosure provides that measuring the ratio of AcH3 and H3 pan not only gives the level of acetylated H3, but also indicates the number of histone octamers in the regulatory regions of the gene. Thus, an ordinarily skilled artisan would be motivated to use the ratio of AcH3 and H3 to select cells have higher acetylation level and also a more open chromatin such that the clones would be more stable and producing higher levels of the recombinant protein by measuring chromatin-antibody precipitates, amplification of the precipitates as well as a non-treated chromatin aliquot, and determining the histone 3 acetylation level. The level of skill in the molecular biology art is high. Absent evidence to the contrary, the ordinarily skilled in the art would have reasonable expectation of success to determine both the methylation frequency and acetylation level in a cell population to select a clone that has high stability in long term culture. One of ordinary skill in the art would have been motivated to use AcH3/H3 ratio to determine H3 acetylation level in order to select a high producing, long term producing cell clone/cell line. It would also been well within the purview of an ordinarily skilled artisan, following instruction disclosed by Urbanucci to include a reference gene, which would have been routine experimentation to an ordinarily skilled artisan. It would also have been obvious to one with ordinary skill in the art to use two sets of the same type of skills in the method disclosed and suggested by Goepfert, Parades, and Urbanucci because this would provide for a reproducible, accurate, and comparable set of data, which can then be used to select the cell clone/cell line having the longest term, highest protein production, which is desirable when selecting a cell clone/cell line for the production of therapeutic proteins, such as antibodies.
Therefore, the claimed invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over Goepfert in view of Parades and Urbanucci, as applied to claims 1-8, 11-15, and 18-20 above, and further in view of McGowan et al. (6(2) PLoS ONE e14739, 1-11 (2011)).
Goepfert, Parades, and Urbanucci disclose and suggest a method for selecting a cell clone/cell line, as discussed above.
Goepfert, Parades, and Urbanucci fail to disclose or suggest that histone 3 acetylation be measured relative to a reference gene, such as gusB.
McGowan discloses using a high-density oligonucleotide array to determine the state of DNA methylation and histone acetylation and gene expression in rats (abstract). McGowan discloses the use of a reference gene, which was selected as being a gene that showed the least variance between high and low grooming (HG/LG) page 2, column 1, first full paragraph). McGowan discloses that the reference gene is gusB (paragraph bridging pages 9 and 10).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to use McGowan’s gusB reference gene in the method of Goepfert, Parades, and Urbanucci because McGowan is determining methylation status and histone acetylation, as does the combination of Goepfert, Parades, and Urbanucci. One of ordinary skill in the art would have been motivated to use McGowan’s gusB reference gene because it show the least variation between groups being tested and analyzed. As such, using the least variable reference gene provides for a more reproducible and accurate measure of CpG methylation and histone acetylation.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-8, 11-15, and 18-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 10,151,002 in view of Paredes et al. (35 Biotechnology Letters 987-993 (2013), and cited in the Information Disclosure Statement filed April 15, 20222) and Urbanucci et al. (72(11) The Prostate 1223-1232 (2012), and cited in the Information Disclosure Statement filed April 15, 2022).
Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘002 patent claims a method for enriching cell clones for expressing a polypeptide comprising determine the methylation frequency of a CpG-site at position 425 of SEQ ID NO: 1 of a nucleic acid comprising a structural gene and a promoter having the sequence of SEQ ID NO: 1 based on the methylation of at least 10 copies of the nucleic acid. The ‘002 patent claims that the methylation frequence is below 5%. The ‘002 patent claims performing polymerase chain reaction using primers that include SEQ ID NOS: 9, 11, and 18. The ‘002 patent claims that the selected cell clone is a Chinese Hamster Ovary (CHO) cell.
The ‘002 patent fails to claim that the selection is based on acetylation of histone
3 (H3) and the ratio of histone 3 acetylation and the level of histone 3. The ‘002 patent fails to claim the location of the histone 3 acetylation in relation to the location of the promoter. The ‘002 patent fails to explicitly claim the use of two groups of the same type.
Paredes discloses that the gradual loss of recombinant protein expression in CHO cell lines during prolonged subculture is a common issue, which seriously affects the industrial
production processes of therapeutic proteins (abstract). Paredes discloses that loss of recombinant copies due to genetic instability of CHO cells, and epigenetic silencing of transgene sequences are main
causes of production instability (abstract).
Paredes discloses that decrease in H3 acetylation in close to transcription start site (TSS) result in instability of producing recombinant antibodies in CHO cells (page 992, first column, Figure 3 and legend). Paredes discloses that the level of H3ac at recombinant sequences seems to be important for the stability of recombinant protein expression during prolonged culture (page 992, column 1, first paragraph).
Urbanucci discloses the amount of total H3 has been used as a measure of nucleosome
density (page 1230, column 1, first paragraph). Urbanucci discloses that measuring the ratio
of AcH3 and H3 pan indicates the number of histone octamers in the regulatory regions of the
gene, whereas a higher ratio of AcH3 and H3 pan indicates a reduced number of nucleosomes in
the regulatory region, which provides a more open chromatin. Urbanucci discloses that H3 acetylation relive transcriptional repression given by nucleosomal positioning (page 1230, column 1, first paragraph).
It would have been obvious to an ordinary skilled in the art before the effective filing date of the claimed invention that when choosing a cell/clone for producing recombinant protein, stability and epigenetic silencing is among the important factors that determines the long term recombinant production based on the ‘002 patent and Paredes The ordinary skilled in the art would thus be motivated to pick a clone that has 5% less methylation at position 425 of SEQ ID NO:1 as claimed by the ‘002 patent and also show higher level of acetylation of H3 as taught by Paredes because such clone
will have stability as demonstrated by Paredes. In addition, one of ordinary skill in the art would be motivated to determine acylation of histone 3 at locations in varying proximity of the transcription start site of the promoter, including within several hundred base pairs, which includes within 200 base pairs upstream of the promoter and transcription start sites, because, as disclosed by Paredes, decrease in H3 acetylation close to the start site causes instability of the cell clones/cell lines. In addition, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to determination of histone 3 acetylation several hundred bases away from the CpG methylation site at position 425 because this allows for accurate measurement of both CpG methylation and histone 3 acetylation without interference with the two analyses. Thus, one of ordinary skill in the art would be motivated to measure H3 acetylation in order to select high-producing, long-term producing cell clones/cell lines. Further, Urbanucci’s disclosure provides that measuring the ratio of AcH3 and H3 pan not only gives the level of acetylated H3, but also indicates the number of histone octamers in the regulatory regions of the gene. Thus, an ordinarily skilled artisan would be motivated to use the ratio of AcH3 and H3 to select cells have higher acetylation level and also a more open chromatin such that the clones would be more stable and producing higher levels of the recombinant protein by measuring chromatin-antibody precipitates, amplification of the precipitates as well as a non-treated chromatin aliquot, and determining the histone 3 acetylation level. The level of skill in the molecular biology art is high. Absent evidence to the contrary, the ordinarily skilled in the art would have reasonable expectation of success to determine both the methylation frequency and acetylation level in a cell population to select a clone that has high stability in long term culture. One of ordinary skill in the art would have been motivated to use AcH3/H3 ratio to determine H3 acetylation level in order to select a high producing, long term producing cell clone/cell line. It would also been well within the purview of an ordinarily skilled artisan, following instruction disclosed by Urbanucci to include a reference gene, which would have been routine experimentation to an ordinarily skilled artisan. It would also have been obvious to one with ordinary skill in the art to use two sets of the same type of skills in the method disclosed and suggested by the ‘002 patent, Parades, and Urbanucci because this would provide for a reproducible, accurate, and comparable set of data, which can then be used to select the cell clone/cell line having the longest term, highest protein production, which is desirable when selecting a cell clone/cell line for the production of therapeutic proteins, such as antibodies.
Claims 9-10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 10,151,002 in view of Paredes and Urbanucci , as applied to claims 1-8, 11-15, and 18-20 above, and further in view of McGowan et al. (6(2) PLoS ONE e14739, 1-11 (2011)).
The ‘002 patent, Parades, and Urbanucci suggest a method for selecting a cell clone/cell line, as discussed above.
The ‘002 patent, Parades, and Urbanucci fail to suggest that histone 3 acetylation be measured relative to a reference gene, such as gusB.
McGowan discloses using a high-density oligonucleotide array to determine the state of DNA methylation and histone acetylation and gene expression in rats (abstract). McGowan discloses the use of a reference gene, which was selected as being a gene that showed the least variance between high and low grooming (HG/LG) page 2, column 1, first full paragraph). McGowan discloses that the reference gene is gusB (paragraph bridging pages 9 and 10).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to use McGowan’s gusB reference gene in the method of the ‘002 patent, Parades, and Urbanucci because McGowan is determining methylation status and histone acetylation, as does the combination of the ‘002 patent, Parades, and Urbanucci. One of ordinary skill in the art would have been motivated to use McGowan’s gusB reference gene because it show the least variation between groups being tested and analyzed. As such, using the least variable reference gene provides for a more reproducible and accurate measure of CpG methylation and histone acetylation.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NANCY J LEITH whose telephone number is (313)446-4874. The examiner can normally be reached Monday - Thursday 8:00 AM - 6:30 PM.
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NANCY J. LEITH
Primary Examiner
Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636