Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
This action is in response to papers filed 8/28/2025.
Claims 1-2,6-7,12-13,17-18, 20-27 are pending. Claims 20, 22-23 have been withdrawn. Claims 3-5, 8-11, 14-16, 19 have been cancelled.
The rejections are maintained with response to arguments following.
An action for claims 1-2,6-7,12-13,17-18,21,24-27 is FINAL.
Withdrawn Rejections
The 35 USC 112b rejection made in the previous office action is withdrawn based upon amendments to the claims.
Maintained Claim Rejections - 35 USC § 112
7. 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.
8. Claims 1-2,6-7,12-13,17-18,21,24-27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The amendment to the claims (Claim 1) requires diagnosing the subject with at least 2 fold increase in gene expression of at least FYB as compared to a control with CTCL. The reply asserts that the claims provide a particular limitation and correlation and points to example 2 and figures 2 to 6 for measuring expression (p. 7). Example 2 points to figures 8A-8B and asserts that there are genes that have differences in expression levels between normal and lesioned (p. 75-76). However, this figure only provides a list of genes, the figures and example 2 does not provide support that FYB is at least 2 fold increase in gene expression. Further, with great to figures 2 to 6, although the figures provide changes in expression, there is no indication that FYB is a 2 fold difference and further there is no description in the specification of diagnosis at 2 fold. Further even in the figures it is not clear the changes in fold expression, figure 4 provides FYB however all the bars are at the same level in the table. Paragraph 239 indications that the figure discloses target genes of samples compared to healthy unaffected controls. It is not clear if the fold of change of each bar is supposed to be a CTCL compared to a healthy individual or if one of the bars is the normal level also. Figure 5 appears to discloses detect expression. As such although the generic recitation of increased by 2 fold expression and FYB is provided in the specification is recited, the specification has not provided the recitation that this correlation provides diagnosis of CTCL. Therefore the data provided in the specification is not clear to provide sufficient support for the amendment.
Response to Arguments
The reply traverses the rejection. A summary of the arguetmsn is provided below with response following.
The reply points to particular passages in the specification that provide for the presence of FYB in the panel of target genes and that the at least one target gene is increased at least 2 fold to diagnose CTCL (p. 6). The reply points to paragraph 75 of “in some embodiments the at least one target gene comprises FYB”. The reply points to paragraph 77 “measuring or determining expression levels of one or more target genes may be useful because some microRNAs are dysregulate” (p. 6). The reply states that “in some aspects, CTCL may be diagnosed ….based on upregulated expression of miR326, miR663b, miR711 and or miR 155 (p. 7). The reply points to “the gene expression level of FYB….at least 1 fold, 2 fold….. (p. 7).
The reply asserts that Figure 4 provides a fold change in various genes in two CTCL lesional samples as compared to normal (p. 7). The table in figure 7A provides FYB expression is upregulated in CTCL (p. 8). The reply asserts that figure 4 provides a consistent increase of approximately 30 fold FYB in samples from a CTCL lesion demonstrates a diagnosis (p. 8). The reply asserts that therefore a 2 fold or greater increase in FYB expression as compared to a control sample can be used to diagnose CTCL in a patient (p.8).
These arguetmsn have been reviewed but have not been found persuasive.
The teaching of miRs used to diagnosis CTCL in the specification does not provide any support for the claims are there is no indication that miRs are encompassed by the “at least one gene”. Although the generic recitation of increased by 2 fold expression and FYB is provided in the specification is recited, the specification has not provided the recitation that this correlation provides diagnosis of CTCL. Furthermore even the arguments provided appear to indicate that a detection of at least 30 fold expression was determined in figure 4 and not the claimed 2 fold. There is no support in the specification that 2 fold expression of FYB in any panel of target genes would diagnose.
The reply points to Figure 4, again discloses only that expression in CTCL legions samples are disclosed at 30 fold expression, however, does not provide support that 2 fold FYB within a panel of target genes provide diagnosis of CTCL. The specification states that figure 7A is a chart including gene expression data from lesional and nonlesional skin (para 16). This figure does not provide any diagnosis but rather provides that there are expression differences between two types of skin.
Figure 2 shows the expression of 17 genes tested in lesioned, nonlesional and healthy unaffected control skin samples (para 11). There is no recitation in the specification that these 17 genes listed have 2 fold increase. The reply asserts that figure 2 provides that numerous genes are increased at least 2 folded including ITK, STAT5, MMP12 and LCK. Although one embodiment would be at least one of these genes are within the panel, there is no indication in the specification that these have a 2 fold increase and diagnosis CTCL. As such the new matter has been maintained.
Maintained Claim Rejections - 35 USC § 112
9. 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.
10. Claims 1-2,6-7,12-13,17-18,21,24-27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for determining expression of a panel of target genes which comprises at least FYB, does not reasonably provide enablement for diagnosing CTCL wherein there is at least one target gene are increased at least 2 fold compared to the sample. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support determination that a disclosure does not satisfy the enablement requirements and whether any necessary experimentation is undue. These factors have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.”
The breadth of the claims and nature of the invention
The claims require measuring expression level of a panel of target genes of the skin sample wherein the panel includes at least FYB, identifying at least one target gene are increased at least 2 fold compared to a control, and diagnosing the subject with the at least two folded increase in gene expression as having CTCL.
Based upon the remarks in the reply, although one interpretation is that FYB is 2 fold, the other interpretation is any of the other potential genes encompassed by “at least one target gene” is 2 fold (see remarks page 5).
Therefore the claims as written encompass unpredictability wherein the guidance in the specification and the teachings of the art does not enable the skilled artisan to make or use the method as claimed.
Nature of the Invention
The invention is in a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
Guidance in the Specification and working examples
The specification provides methods of qRT PCR to determine expression patterns (p 72-74). The specification points to figure 2 as providing 17 exemplary genes in lesioned, nonlesional and healthy unaffected controls (para 237). Figure 3 provides expression of targets genes normalized to housekeeping and figure 4 fold change of target genes in CTCL lesioned skin samples (p. 75). Example 2 of the instant specification provides in the figures the gene expression changes in patients with lesioned versus normal (p. 76). The specification asserts that the data indicates that 8 genes may be used for a CTCL rule out test(para 243). However, the specification does not provide any guidance to using at least one gene in a panel that has 2 fold or greater expression to diagnosis CTCL. Further, there is no indication that FYB expression can diagnosis CTCL. Although there appears to be associations of expression of particular genes and ruling out CTCL, this guidance does not provide support for the claimed method which diagnosis CTCL based upon 2 fold expression of any at least one gene from a gene panel.
The unpredictability of the art
The art teaches genetic variations and associations are often irreproducible. Hirschhorn et al. (Genetics in Medicine. Vol. 4, No. 2, pages 45-61, March 2002) teaches that most reported associations are not robust. Of the 166 associations studied three or more times, only 6 have been consistently replicated. Hirschhorn et al. suggest a number of reasons for the irreproducibility of studies, suggesting population stratification, linkage disequilibrium, gene-gene or gene-environment interactions, and weak genetic effects and lack of power are possible factors that lead to such irreproducibility. Hirschhorn et al. caution that the current irreproducibility of most association studies should raise a cautionary alarm when considering their use as diagnostics and prognostics (p. 60, Col. 2). Thus, Hirschhorn cautions in drawing conclusions from a single report of an association between a gene and a disease type (in this instance diagnosis).
The level of skill in the art
The level of skill in the art is deemed to be high.
Quantity of Experimentation
The nature of the invention not only involves detection of at least 2 fold of FYB expression but also other embodiments wherein unnamed genes in the panel have at least 2 fold expression and diagnosis of CTCL. The specification has not provided guidance as to which gene would be encompassed in the panel and would not be encompassed. Further, the specification has not provided guidance for diagnosis of CTCL based upon any of these genes having 2 fold expression. The art teaches that such associations are unpredictable and require large data sets that are analyzed multiple times.
Therefore the claims are written would require undue experimentation with no expectation of success.
Conclusion
Given the markers disclosed in the specification are unpredictable with regard to epistatic interactions, wherein some have an interaction and others do not. Given that there is no guidance as how to correlate such expression with diagnosis of CTCL. Given that the art teaches such associations are unpredictable. The skilled artisan would have to perform undue experimentation to practice the invention as claimed.
Thus given the broad claims in an art whose nature is unpredictable, the unpredictability of that art, the large quantity of research required to define these unpredictable variables, the lack of guidance provided in the specification, and the negative teachings in the prior art balanced only against the high skill level in the art, it is the position of the examiner that it would require undue experimentation for one of skill in the art to perform the methods of the claims as broadly written.
Response to Arguments
The reply traverses the rejection. A summary of the arguetmsn is provided below with response following. The reply asserts that that the claims have been amended to clarify that at least one target gene is increased at least 2 fold compared to the control sample comprises FYB (p. 9). The reply points to Figure 4 and 7A to show that a 2 fold FYB expression correlated with CTCL diagnosis (p. 9). These arguetmsn have been reviewed but have not been found persuasive. The specification asserts that the data indicates that 8 genes may be used for a CTCL rule out test(para 243). However, the specification does not provide any guidance to using at least one gene in a panel that has 2 fold or greater expression to diagnosis CTCL. Further, there is no indication that FYB expression can diagnosis CTCL. Although there appears to be associations of expression of particular genes and ruling out CTCL, this guidance does not provide support for the claimed method which diagnosis CTCL based upon 2 fold expression of any at least one gene from a gene panel. The reply points to Figure 4, again discloses only that expression in CTCL legions samples are disclosed at 30 fold expression, however, does not provide support that 2 fold FYB within a panel of target genes provide diagnosis of CTCL. The specification states that figure 7A is a chart including gene expression data from lesional and nonlesional skin (para 16). This figure does not provide any diagnosis but rather provides that there are expression differences between two types of skin. It is noted that the figures and example might provided guidance for increased risk, however, there is no example in the specification that provides a diagnosis of CTCL based upon the detection of the claimed gene panel. The specification does not provide guidance to predictably detect CTCL in a panel that has at least 2 fold increase of FYB.
Conclusion
11. No claims are allowed.
12. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE D SALMON whose telephone number is (571)272-3316. The examiner can normally be reached 9-530.
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/KATHERINE D SALMON/ Primary Examiner, Art Unit 1682