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 .
Applicant’s response to restriction letter of 6/30/26 is acknowledged. Applicant elected Group I (claims 1, 3-6, 8-14 and 16-18), drawn to a method of determining a quantitative value of the ability of a biological sample to lake up low-density lipoprotein (LDL), a method of Group I wherein lipid lowering therapy involves statin therapy, (species (i)), with traverse.
Claims 2, 7, 15, and 19 and species (ii)-(iv) are hereby withdrawn.
In traversal of restriction requirement, applicant argues that instant method measures one or more of the “quantitative values” defined in claim 1, and subjects with one or more quantitative values defined are likely to achieve their target goals with the lipid lowering therapy, while other subjects are not. This may allow people to quickly identify subjects who are not likely to respond to a certain lipid lowering therapy.
Pocathikorn et al., measured LDLR mRNA expression after atorvastatin treatment. Contrary to examiner’s opinion, said reference does not disclose a “quantitative value” of the ability of cells to uptake LDL. LDLR mRNA is not a measure for LDL uptake. Further Pocathikorn does not suggest there would be any link between LDLR mRNA expression and atorvastatin induced LDL-C (LDL-cholesterol) lowering. Therefore, the unity of invention exists, and restriction should be withdrawn.
These arguments were fully considered but were found to be unpersuasive.
This is because, it is unclear what exactly applicant means by “quantitative values”. Applicant has not provided any specific definition by said phrase (see 112 second rejection below) and no numerical values are indicated in the claims. Therefore, in the absence of a specific definition of said phrase, the examiner maintains that Pocathikorn in Table 3 shows “quantitative values “such as mRNA expression levels of LDLR and LDLR related proteins.
Further, in contrast to applicant’s view, Pocathikorn does not need to suggest a link between LDLR mRNA and LDL uptake because one of ordinary skill in the art is aware that overexpression of LDLR mRNA, results in production of LDL receptors, which end up on the surface of mononuclear cells of Pocathikorn. Since said surface receptors inherently bind LDL in the blood stream, it is reasonable to one of ordinary skill to conclude that at first glance, Atorvastatin treatment of hyperlipidemic patients, which produces more LDL receptors on the surface of his/her bloods cells, will result in binding more LDL in the patients’ blood stream, thereby lowering their LDL levels.
Furthermore, Pocathikorn is not the only art that anticipates or renders this invention obvious, and the examiner will cite additional art below to challenge the patentability of this invention.
In conclusion, in view of arguments provided above, in addition to those discussed previously restriction is maintained and is hereby made Final.
DETAILED ACTION
Claims 1, 3-6, 8-14 and 16-18 and only Group A invention and species (i) are under examination on the merits.
Specification
The disclosure is objected to for reciting hyperlink language (see for example page 26, line 11). Applicant is advised to delete hyperlink language everywhere in the disclosure, in compliance with 37 CFR section 1.57(d).
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, 3-6, 8-14, 16-18 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. The phrase “quantitative value” is confusing because it is generic and non-specific. Applicant has not defined said phrase in the disclosure and it is unknown if said value is referring to a value above/below a threshold value, a multi-parametric value, a uni-parametric value, or something else. Further, in claims 1, 3-6, 8-13, 16-18, it is unknown if said value is normalized or not etc. and what are the specific numerical values associated with said phrase. Furthermore, it is totally unknown what physical/chemical features of blood cells (such as cell size, cell density, cell chemistry etc.) was measured to determine the “quantitative value”.
In addition, in claim 1, the term “lipid” has a broader scope that low-density (LDL) cholesterol. It is unclear what applicant means by “lipid lowering therapy”. If said therapy is directed to “LDL lowering therapy” the applicant must substitute “lipid lowering therapy” with said latter phrase for clarity. Claims 3-6, 8-14, 16-18 are merely rejected for depending from claim 1.
Claims 3, 16-18 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. In claim 3 line 8, and claim 16, line 6 and lines 10-11, the phrase “quantitative value of the expression of LDLR” and “the quantitative value of the expression of LDLR”, respectively, lack antecedent basis.
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.
Claim(s) 1, 3-6, 8-14, 16-18 are rejected under 35 U.S.C. 102(a)(2) as anticipated by Brown et al., “Brown” (US 2019/0227085, 7/2019) or, in the alternative, under 35 U.S.C. 103 as obvious over Brown. Said patent publication in its abstract teaches about methods of using blood-based biomarkers and their combinations to identify patients at risk of having cardiovascular disease (e.g. coronary, atherosclerosis).
In [0006-0007] according to Brown:
“[0006] Provided herein are methods of predicting the presence, and/or the risk of cardiovascular disease in a human subject that include: determining the levels of LDL-TG in a blood sample obtained from a subject; and identifying the subject as having, or being at risk of having cardiovascular disease if the level of LDL-TG is elevated as compared to a control level.
[0007] In some embodiments of any the methods described herein, the method can further include determining the level of at least one analyte in the blood sample obtained from the subject, wherein the at least one analyte is selected from the group consisting of: triglycerides, total cholesterol, low density lipoprotein (LDL)-cholesterol, high density lipoprotein (HDL)-cholesterol, apolipoprotein B (apoB), interleukin 6 (IL-6), symmetric dimethylarginine (SDMA), apolipoprotein B48 (apoB48), palmitoleic acid (POA), small dense LDL (sd-LDL), alkaline phosphatase (ALP) and asymmetric dimethylarginine (ADMA), and identifying the subject as having or being at risk of having cardiovascular disease if the levels of LDL-TG and the at least one analyte are both elevated as compared to a control level.”.
In [0036-0037], Brown discloses the following:
“[0036] As used herein, “obtain” or “obtaining” can be any means whereby one comes into possession of the sample by “direct” or “indirect” means. Directly obtaining a sample means performing a process (e.g., performing a physical method such as extraction) to obtain the sample. Indirectly obtaining a sample refers to receiving the sample from another party or source (e.g., a third party laboratory that directly acquired the sample). Directly obtaining a sample includes performing a process that includes a physical change in a physical substance, e.g., a starting material, such as a blood, e.g., blood that was previously isolated from a patient. Thus, obtain is used to mean collection and/or removal of the sample from the subject. Furthermore, “obtain” is also used to mean where one receives the sample from another who was in possession of the sample previously.
[0037] In some embodiments, the reference sample is obtained from at least one individual not suffering from cardiovascular disease. In some other embodiments, the reference sample is obtained from at least one individual previously diagnosed as having cardiovascular disease (e.g., atherosclerotic coronary artery disease (ASCAD) or a coronary atherosclerotic plaque). In some embodiments, the reference sample comprises a predetermined, statistically significant reference analyte levels. In some embodiments, the methods further comprise performing a comparison between the measured levels of one or more analytes in the biological sample with one or more reference samples, wherein the reference sample is obtained from a matched (e.g., age, gender, etc.) human subject.”.
In [0062-0087] methods of predicting the likelihood of the presence of cardiovascular disease and the risk of cardiovascular disease in a human subject that include: determining the level of LDL-TG in a biological sample (e.g., a blood sample) obtained from a subject, alone or in combination with at least one analyte is selected from the group consisting of: triglycerides, total cholesterol, low density lipoprotein (LDL)-cholesterol, high density lipoprotein (HDL)-cholesterol, apolipoprotein B (apoB), interleukin 6 (IL-6), symmetric dimethylarginine (SDMA), apolipoprotein B48 (apoB48), palmitoleic acid (POA), small dense LDL (sd-LDL), alkaline phosphatase (ALP) and asymmetric dimethylarginine (ADMA); and identifying the subject as being at risk of having cardiovascular disease if the level of the at least one analyte is elevated as compared to a control level etc. are discussed.
In [0088-0098], determination methods utilized by Brown are elaborated. In [0091], reference is made to imaging and fluorescent detection together with automation etc.
In Example 3, [0135], according to said publication, the primary result and output from unbiased Bayesian network analysis is shown in FIG. 4. The ensemble of Bayesian networks identified from the data consisted of 24,929 nodes and 110,350 edges occurring in more than 5% of models in the ensemble. The results indicated that LDL-TG was the only biomarker directly upstream from the presence of atherosclerotic CAD, occurring in 95% of networks in the ensemble. This suggested a potential causal role of TG-rich LDL particles, as measured by LDL-TG's, in atherosclerosis. Given the central role of LDL-TG in the Bayesian networks, attention was focused on LDL-TG to further elucidate its potential contribution to atherosclerosis.
In [0128], Brown indicates whole genome sequencing, DNA methylation analysis of approximately 450,000 sites, and quantification of ˜28,000 mRNA's and ˜6,000 micro-RNA's from circulating mononuclear cells, ˜1,800 proteins, ˜800 metabolites and ˜150 complex lipid species were performed.
In [0137] and [0140], Brown recites:
“[0137] To examine the relative contribution of each of the key measurements to atherosclerosis, cumulative incidence curves were constructed for ApoB, LDL-C and LDL-TG against the cumulative incidence of atherosclerosis in all subjects, and also in subjects not on statins at the time of the study visit (FIG. 5). Cumulative incidence curves (CIC) demonstrated the well-described “sigmoid” relationship between ApoB and LDL-C levels, mostly in the ApoB range of 50-150 mg/dL and in the LDL-C range of 60-200 mg/dL. The curves were significantly influenced in statin-treated patients (FIGS. 5A-B), where the cumulative incidence of atherosclerosis was high despite very low levels of ApoB (FIG. 5A) and LDL-C (FIG. 5B), likely representing patients with known CAD and aggressive statin therapy. The “sigmoid” relationship for ApoB and LDL-C was more apparent when statin-treated patients were excluded (FIGS. 5D-E). On the other hand, a clear, “sigmoid”, or “near exponential” relationship was seen as a function of serum LDL-TG levels, with no apparent effect of statin therapy (FIG. C and FIG. 5F). The left tails of the CIC curves were highly influenced by patients with known CAD whose LDL-C and ApoB-levels were likely lowered by recent statin therapy, showing a high cumulative incidence of CAD at very low levels of LDL-C and ApoB. Importantly, statin therapy appeared to have little influence on the cumulative incidence of CAD as a function of LDL-TG measurements (FIG. 5 C and FIG. 5F).
[0140] Interestingly, while the left tail of the LDL-C and ApoB cumulative incidence curves (see Figure 5) were heavily influenced by patients with known CAD in whom lipid-lowering therapy was used to lower these biomarkers, LDL-TG measurements were largely independent of the effect of statin therapy, suggesting that LDL-TG measurements might be more reliable in the detection of atherosclerotic CAD in subjects on statin treatment for high LDL-C levels.”
Therefore, by reading Brown’s teachings above and as a whole, one of skill in the art, before the effective filing of this application, would reasonably conclude that in people or patients with cardiovascular disease (many of whom inherently having hyperlipidemia) , who have high levels of LDL-TG in their blood, statin lipid lowering therapy which only operates to lower LDL cholesterol levels will be ineffective as Brown’s data shows that the likelihood of cardiovascular disease is directly related to LDL-TG levels and statin is unable to lower the levels of LDL-TG, anticipating this invention, or in the least rendering it obvious.
With regards to claim 5, in view of the fact that Brown mentions blood samples everywhere in its disclosure looking for the effect of lipid lowering therapy in all and every cells constituting blood of the patient, is readily obvious.
Considering claims 13 and 17, it is unclear how “LDL snap freezing “of subject blood cells has any impact on the method claimed and hence, said claims are also combined with other elected claims under rejection.
Similarly, in claims 10, 16 and 18, the impact of how the blood cells in the sample are presented (i.e. monolayer vs liquid (solution) state etc.) for imaging analyses (whatever the imaging techniques are) and how many different blood cell types were independently or group wise analyzed etc. in view of ambiguity of the technique utilized for “quantitative measurements” cannot be determined and hence, said claims are also ae included in this rejection.
No claim is allowed.
Note:
The following patent publication may be of relevance to this invention:
Damask et al., US2021/0002724, 1/2021.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARYAM MONSHIPOURI whose telephone number is (571)272-0932. The examiner can normally be reached full-flex.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melenie L Gordon can be reached at 571-272-8037. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MARYAM MONSHIPOURI/Primary Examiner, Art Unit 1651
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