DETAILED ACTION
The present application is being examined under the pre-AIA first to invent provisions.
This action is in response to the papers filed May 26, 2026. Currently, claims 1, 10, 12-17 are pending. Claims 10, 12-15 are withdrawn as drawn to non-elected subject matter. Applicant elected a combination of genes which includes Acaca and Nampt (see paper filed December 27, 2021). Claims 10, 12-15 are not directed to the elected combination.
All arguments have been thoroughly reviewed but are deemed non-persuasive for the reasons which follow.
Any objections and rejections not reiterated below are hereby withdrawn.
The 103 rejection over Sharov in view of Gabrielson has been withdrawn as the analysis was performed in gonads rather than white adipose tissue, as now required by the claims.
The new Matter rejection has been withdrawn in view of the amendments to the claims to remove the control white adipose tissues has not been administered a compound.
The 101 rejection has been withdrawn in view of the amendments to the claims to require manufacturing a formulation with the candidate compounds that were selected.
Priority
This application claims priority to divisional application 13/525,230 filed June 15, 2012 and provisional application 61/497,476, filed June 15, 2011.
Drawings
The drawings are acceptable.
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 negatived by the manner in which the invention was made.
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 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.
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).
Claims 1, 16-17 is/are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Zhao-Wilson et al. (WO2007-109102, September 2007) in view of Franck et al. (J. of Clinical Endocrinology & Metabolism, Vol. 96, No. 2, pages e413-418, February 2011) or Masafumi Aoki (JP2012/115374A, June 21, 2012) and further in view of Iami et al. (US 2007/0082373, April 12, 2007) or Yang et al. (Experimental Gerontology, Vol. 41, No. 8, pages 718-726, August 2006) in view of Gabrielson et al (Modern Pathology, Vol 14, No. 12, pages 1294-1299, 2001).
The claims require probes that are labeled with a chemiluminescent or radioactive label. The nucleic acids in the samples hybridized to the arrays are labeled. These nucleic acids are considered probes.
Zhao-Wilson teaches testing and screening for caloric restriction (CR) mimetics, single compounds (page 4). Zhao-Wilson illustrates, in Figure 1, administering to a subject a CR mimetic as part of an intervention and monitoring the intervention effect of the CR mimetic (Figure 1). Zhao-Wilson teaches the administrating steps are designed to determine whether a CR mimetic candidate is a CR mimetic; for example, comparing levels of biological parameters of known CR markers to measurements of the known CR markers from the subject having been administered the CR mimetic candidate. Zhao-Wilson teaches grape extract may be tested as a CR mimetic by obtaining measurements of gene expression levels of known CR markers in subjects receiving grape extract and comparing those measurements to known gene expression levels, induced by a CR diet, of the known CR markers (page 4-5). Zhao-Wilson teaches known CR markers include genes known to be effected (e.g effected in gene expression levels) by a CR diet or a known CR mimetic or gene products of such genes or metabolites (page 7-8). Figure 1 illustrates if the subject is predicted to be a good candidate, administer a CR mimetic and monitor the CR mimetic being administered and repeat the process. Thus, Zhao-Wilson teaches administering a candidate compound that was selected which is necessarily in a formulation.
Zhao-Wilson does not teach analysis of ACACA and Nampt in white adipose tissue.
However, Franck teaches identifying adipocyte genes regulated by caloric intake. Franck teaches identifying genes that were differentially expressed by caloric restriction. Franck specifically teaches adipose tissue has a key role in energy storage and is also a major endocrine organ. Franck teaches analysis of caloric restriction in adipose tissue to search for adipocyte genes regulated by change in caloric intake in adipose tissue. Franck teaches adipose tissue undergoes dramatic change when caloric intake is altered, including changes in gene expression. Among these genes was Acaca (abstract). Franck studied human participants to analyze adipose tissue biopsies for DNA microarray analysis (page e414, col 1). Franck teaches microarray results may be confirmed with real-time PCR analysis. Table 1, page E415, col 1 lists ACACA as gene positively regulated by caloric intake in adipocyte genes. Supplemental Table 2 clearly provides that significance of Acaca in caloric restriction.
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Even more, the abstract of Franck further identifies Acaca as one of the significant genes. Thus, the list of genes is much smaller than 102, but is directed to 8 genes. Franck teaches using microarrays for analysis. The nature of microarrays is particular probes are immobilized on a solid support in an organized manner to allow clear identification of particular genes according to the probe coordinates. Thus, Franck necessarily uses a probe for hybridizing to Acaca.
Masafumi teaches methods of determining ACACA expression in white adipose tissue. Masafumi teaches analyzing expression patterns following treatment with thermal stimulation. Masafumi finds that ACACA expression was significantly reduced in white adipose tissue following treatment. The treatment has an effect of suppressing fat accumulation in the living body through inhibition of fatty acid synthesis and is considered to be effective in preventing or improving obesity and lifestyle-related diseases.
Additionally, Imai provides an examination of Nampt production and secretion in primary white and brown adipose tissues in response to nutritional, hormonal and pharmacological stimuli (see Example 22, para 251). Imai teaches white adipose tissue was isolated from mice and tissue was prepared. Imai teaches levels of Nampt in white adipose tissue will be determined after treatments also (para 252). Imai teaches total RNA was purified from white adipose tissue and RT-PCR was performed using SYBR geen PCR (para 264). Imai teaches specifically studying Nampt response to stimuli and compounds.
Yang teaches analysis of Nampt/PBEF/Visfatin. Yang teaches Nampt is expressed in visceral fat, a type of white adipose tissue (page 5, para 3). Yang also teaches plasma Nampt levels correlated with the amount of visceral fat in human subjects (page 5, para 3). Visceral fat is white adipose tissue. Visceral fat, also known as "belly fat" or "organ fat," is a type of white adipose tissue (WAT) stored within the abdominal cavity, surrounding vital organs. Yang teaches Nampt modulates cell survival in the same way CR does (page 6, para 5). Yang teaches Nampt (PBEF/Visfatin) is upregulated by nutrient depravation, caloric restriction (CR) and other forms of mild stress (see Figure 4).
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Yang unequivocally suggests Nampt levels may be mimic aspects of CR.
Before the claimed invention, the ordinary artisan would have been motivated to have screened compounds for efficacy by detecting differential gene expression associated with caloric restriction as taught by Zhao-Wilson, such as Acaca and Nampt in white adipose tissue as taught by Franck, Masafumi, Imai and Yang. The teachings of Masafumi and Imai are focused solely on Acaca and Nampt respectively. Combining analysis of these two genes into a single assay would have been obvious to the ordinary artisan. MPEP 2144.06 provides "[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Here, both Nampt and Acaca were identified as differentially expressed and associated with caloric restriction. Thus, the instant invention provides a method for analyzing two genes that were previously known to be associated with caloric restriction. Zhao-Wilson teaches screening for CR mimetics that may be used for CR by administering single compounds to subjects and analyzing the gene expression of known CR markers. The art teaches Nampt and Acaca are known CR markers and analyzes their expression in white adipose tissues (WAT). It would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to have modified the methods for analyzing a single compound for CR, as taught by Zhao-Wilson to have surveyed Nampt and Acaca as taught by Franck, Masafumi, Yang and Imai. The art teaches Nampt and Acaca to be associated with caloric restriction and adipose expression. The ordinary artisan would have been motivated to provide analysis of gene expression associated with caloric restriction. It is prima facie obvious to combine elements, each of which is taught by the prior art to be useful for the same purpose. Here there was a reasonable expectation of success that analysis of Nampt and Acaca would result in determining a compound was differentially expressed and a formulation could be manufactured. Obviousness does not require absolute predictability of success.
Here, the selection of Acaca and Nampt would be obvious to try. This is not a situation of picking and choosing or a laundry list. Masafumi is solely directed to Acaca gene expression in white adipose tissue following treatments. Imai is specifically directed to compound analysis of Nampt in white adipose tissue with RT-PCR that relies upon hybridization. The response does not identify a secondary consideration demonstrating criticality or anything unexpected about the combination of two known biomarkers. Instead, this is a situation of obvious to try. The analysis of biomarkers for caloric restriction was an art recognized problem that many skilled artisans were studying, including studying Acaca and Nampt. Thus, there was an art recognized problem. The art teaches a finite number of markers. The cited art here specifically identifies Acaca and Nampt as associated with caloric restriction. Applicant does not identify a secondary consideration demonstrating criticality or anything unexpected about the combination of two known prior art caloric restriction markers.
Further, Neither Yang nor Zhao-Wilson nor Franck, Imai, nor Masafumi specifically teach how the nucleic acids are labeled.
However, Gabrielson teaches gene expression measurements on arrays may be made using two-color fluorescence or radiolabeling. Gabrielson teaches two general options are available for sample labeling: radionucleotide labeling and fluorescent labeling. The level of RNA for each gene in the sample is measured as intensity of radioactivity binding to the specific spot. Gabrielson teaches the major advantage of radiolabeling is the high level of sensitivity that allows analysis of small tissue samples without amplification of the RNA sample.
Therefore, it would have been prima facie obvious at the time the invention was made to have modified the gene expression analysis method of Yang, Zhao-Wilson and Franck to replace the fluorescent labeled sample nucleic acid probes with a radioactive label as taught by Gabrielson. The art teaches radiolabeling and fluorescent labeling are both known techniques for detecting gene expression on microarrays. Thus, substituting fluorescent labels for radioactive labels would have been prima facie obvious for the predictable result of detecting gene expression.
Even more, Gabrielson specifically teaches the major advantage of radiolabeling is the high level of sensitivity that allows analysis of small tissue samples without amplification of the RNA sample. Therefore, the ordinary artisan would have been motivated to have used radiolabeling for the expected benefits taught by Gabrielson.
Response to Arguments
The response acknowledges the primary references of Zhao-Wilson teaches the broad concept of testing or monitoring caloric-restriction mimetics and measure gene-expression measurements. The response however correctly states Zhao-Wilson does not identify Acaca and Nampt as biomarkers in white adipose tissue. This argument has been reviewed but is not persuasive because the additional references that provide the foundation of the rejection teach Acaca and Nampt as biomarkers in white adipose tissue. The art, namely Masafumi and Imai, are specifically directed to analyzing only Acaca and Nampt respectively. Therefore, combining these references would yield the combination of two universal biomarkers of caloric restriction.
The response argues the references do not teach or suggest a combination of Acaca and Nampt. The response again acknowledges Acaca is within a list of adipocyte genes associated with changes in caloric intake but Franck does not teach selection Acaca in combination with Nampt for determining whether a candidate compound mimics caloric restriction. Masafumi is also directed to suppressing Acaca expression in fat tissue for analysis. Imai and Yang are directed to analysis of Nampt in metabolic contexts. The response concludes that none of the cited references teach combining Nampt expression together with Acaca expression in white adipose tissue. This argument has been reviewed but is not persuasive. This argument has been reviewed but is not persuasive. The references cited teach each of the genes is individually associated with expression in white adipose tissue and their differential expression in response to compounds associated with adipose tissue. The combination of two known genes into a single assay would provide increased benefits of determining a better picture of effect of a particular compound on effects of calorie restrictions. As provided in MPEP 2144.06, combining two compositions each of which is taught by the prior art to be useful for the Same purpose in order to form a third composition to be used for the same purpose is prima facie obvious. Here, the art teaches analysis of Acaca and Nampt for the same purpose of being associated with metabolic /caloric restriction. Thus, combining the two genes in a screening assay to determine compounds that affect caloric restrictions would have been prima facie obvious at the time the invention was made.
The response finally argues the rejection relies upon hindsight. The response argues a person of ordinary skill in the art would have no reason to choose Acaca and Nampt from among the 35,000 genes in the human genome. This argument has been reviewed but is not persuasive. Applicants may argue that the examiner’s conclusion of obviousness is based on improper hindsight reasoning. However, "[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper." In re McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971). The art taught each of the genes was associated with caloric restriction and metabolic profiles.
The response filed June 23, 2025 argues that the MPEP 2112 is directed to inherency principle application to compositions and not methods. This argument has been reviewed but is not persuasive. MPEP 2112.02 is directed to the principle of inherency in process claims. The response cites MPEP 2112.02(II) however, the citation states that “when the claim recites using an old composition and the “use” is directed to a result or property of that composition or structure, then the claim is anticipated. Here, the inherent property is Acaca and Nampt as universal biomarkers of caloric restriction and the use is directed to using the Acaca and Nampt genes, thus, the recitation is inherent and the claims are obvious.
The use of probes that hybridize to Acaca and Nampt was obvious. While the prior art did not recognize Acaca and Nampt as “universal” biomarkers of caloric restriction, the use of Acaca and Nampt was “old.” As provided by MPEP 211.02(II) “[w]hile the references do not show a specific recognition of that result, its discovery by appellants is tantamount only to finding a property in the old composition.” 363 F.2d at 934, 150 USPQ at 628 (emphasis in original)). Thus, adding a recitation of a “new” property or “universal biomarker” to and “old” product does not render the claims patentable.
The response previously argued secondary considerations and stated that the specification indicates that “universal CR biomarkers…correlated to a CR response across multiple different, genetically diverse, strains of animals”. To support this position of multiple different strains and genetically diverse animals, the specification assesses 7 different strains of mice. This showing in a single species is not commensurate in scope over the full scope of the claims that require canine, feline and human subjects. The showing of 7 different mice is not evidence that the genes are universal markers for cats, dogs and humans. There is no showing in the specification that the genes are universal biomarkers for CR in human, dogs and cats, for example. Thus, the specification does not provide any evidence that the claimed genes are universal biormarkers of CR that is an unexpected property commensurate in scope with the claims.
Thus, for the reasons above and those already of record, the rejection is maintained.
Conclusion
No claims allowable.
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.
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/JEANINE A GOLDBERG/Primary Examiner, Art Unit 1634 June 15, 2026
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