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 .
Claims 2, 4, 6-8, 14-15 have been canceled.
Claims 1, 5, 5, 9-13 and 16-27 are pending and under examination.
Specification
It is noted that the illustration of Figure 4, page 5, applicants misspell “DIC” with “CID”. Please correct it.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 5, 9-13 and 16-26 are rejected under 35 U.S.C. 101 because the claimed invention is directed to (1) measuring natural molecules from a subject, i.e. SEQ ID No. 1 (LGEYDLR) in samples reflecting the level of protein C, and (2) correlating an association of such level for classifying the subject as being at risk of having sepsis or septic shock. Therefore, the natural relationship is the biomarker(s) correlating with a “condition” under judicial exception. (See Mayo Collaborative Servs. v. Prometheus Laboratories, Inc., 132 S.Ct. 1289 (2012). Note, although independent claims 1, 3 and 16 have different reference level for comparison, nevertheless after all these are still natural intrinsic (endogenous) levels without significantly more. The claim(s) recite(s) judicial exception. This judicial exception is not integrated into a practical application because no additional step is incorporated in the claim. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because The instant steps, such as obtaining samples, measuring SEQ ID No. 1 by spiking a labeled SEQ ID No. 1, wherein the labeled peptide SEQ ID NO. 1 has at least one or more heavy amino acids. The steps are well-understood, routine, conventional activity in the field and add insignificant extra-solution activity to the judicial exception. For instance, Wanner (US 20180364259) teaches spking heavy isotope labeled internal standard peptide (same as target peptide) to ensure quality of quantitation by mass spectrometry (section 0051; 0065). Similarly, Gajadhar (US 20210375604) teaches spiking a known amount of stable isotope labeled standard for mass spectrometry analysis (section 0003). In addition, Jacobs (US 20140273275) discloses the same procedures spiking labeled peptides as internal standard in measuring biomarkers by mass spectrometry (section 0212). Furthermore, Aebersold (US 20060141528) teaches spiking the same isotope labeled internal peptides in analyzing target peptide by mass spectrometry (section 0198-0199). These steps are recited at a high level of generality, and are necessary data gathering steps that feed into the determining step. One cannot do the determining step without getting the data. This weighs against it being significantly more.
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 16-19 and 27 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.
It is noted that claim 16 directs to a mass-spectrometry based method for screening or classifying a subject as being at risk of having sepsis or septic shock which exactly the same as claim 1. However the clinical data disclosed in the specification (Figure 1-4) merely supports embodiment of claim 1 with the reference value. In another word, the threshold of claim 16, i.e. 4000 ng/ml, is contrary to the threshold of protein C in claim 1, i.e. 1431.57 ng/ml. Assuming the threshold value of protein C in claim 16 is true, then most of the “identified” sepsis or septic shock patients in Figure 1-4 would have been “normal”. For the prior art purpose, examiner would consider the data of clinical study from the specification (claim 1).
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 20-22 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.
As to claim 20, line 1, “the enzymatic digestion” lacks antecedent basis.
Similarly claim 21, last line, “the enzymatic digestion” lacks antecedent basis.
Claim Rejections - 35 USC § 103
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.
Claim(s) 1 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Yan (Chest 2001 Vol. 120:915) in view of Sin (US 20190383830) and Wanner (US 20180364259).
Yan teaches that level of protein C is associated with sepsis patients. The study of Yan’s group show that there is a lower level of protein C in the sepsis patient compared to the control one (Abstract; Results). The control reference level is about 1.79-3.87 µg/ml (equal 1790-3870 ng/ml) (Materials and Methods). The reference level reads on claim 1 reference (1431.57 ng/ml). Furthermore, the level has been reduced about 42% in septic shock patients. The calculation is based on normal value (assuming 2.1 µg/ml) versus the mean value of sepsis patient (1.21 µg/ml; Table 2): 2.1-1.21/2.1x100% = 42%. Note, the differences of laboratory methodology, procedures, ingredients and diverse of geographic as well as ethnicity and physical background of the patients may contribute to the different results. Nevertheless the gist of the study shows that levels of protein C in sepsis patients are generally lower. However Yan does not explicitly teach using mass spectrometry analyzing SEQ ID No. 1 (LGEYDLR) specific protein C by spiking isotope labeled SEQ ID No.1 for quantification of protein C.
Sin teaches using mass spectrometry in analyzing protein biomarker specific peptides in a biological samples (see Abstract; Table 4). One of the specific peptide used in mass spectrometry in measuring protein C is SEQ ID No. 260 (same LGEYDLR SEQ ID No. 1) in Table 4. Sin teaches that this particular peptide can be used in measuring protein C in a sample by mass spectrometry.
Wanner teaches spiking a known amount of heavy isotope proteotypic peptide in analyzing target peptide in a sample (section 0015, 0065). Spiking targets molecules is known in the field for quantification and quality control purpose.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the method taught by Sin to measure protein C specific peptide SEQ ID No. 1 by mass spectrometry in coupling with spiking the same labeled peptide with reasonable expectation of success. One ordinary skilled person in the art would have adapted an alternative method other than immunoassay (e.g. antibody), such as mass spectrometry in avoiding cross-reactivity by antibody and increasing specificity by measuring protein C specific peptide SEQ ID No. 1. Moreover, use of spiking labeled target specific peptide for quantification is well-known and commonly practiced in the field (see above 35 USC 101, under “conventional, routine and common” prong). One ordinary skilled person would have been motivated to use this procedure for ensuring quality and increasing precision of the measurement.
As to claim 5, Wanner teaches employing protease digestion, i.e. trypsin, prior for mass spectrometry analysis (section 0111).
Claim(s) 9 is rejected under 35 U.S.C. 103 as being unpatentable over Yan, Sin and Wanner as applied to claims 1 and 5 above, and further in view of El-Sayed (US 20190008964).
The references of Yan, Sin and Wanner have been discussed but none of the references explicitly teaches using both reducing agent, such as dithiothreitol (DTT) followed by alkylating agent, such as iodoacetamide in preventing reforming disulfide bond in the digested polypeptide.
El-Sayed teaches using the above two DTT as well as iodoacetamide for mass spectrometry analysis (section 0207). These two agents are well-known and commonly used in protein chemistry analysis in breaking disulfide bond and preventing reforming of disulfide bond.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the method taught by El-Sayed to have DTT and iodoacetamide adding to the enzymatic digested sample to ensure linear polypeptide for subsequent mass spectrometry analysis.
Claims 3, 10-13, 20-26 are free of prior art but subject to judicial exception as discussed above.
Inventors in the current application have used an improved methodology, i.e. mass-spectrometry in identified disseminated intravascular coagulation (DIC) patients with a more precise reference value, i.e. 600 ng/ml, with a more definite window, i.e. at least 20% reduction (480 ng/ml) as indicative of DIC. Throughout literatures, most of the researchers have found a lower level of protein C associated with DIC, but none has discovered the current reference value together with the at least 20% threshold (480 ng/ml) using heavy amino acid labeled protein mass spectrometry. Takahashi (Thrombosis and Haemostasis 1985 54:445) have observed about 60% activity reduction (not level of ng/ml)(See Figure 2 below).
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Assuming arguendo the level equals the activity, given the normal level of 1790 ng/ml (i.e. 1.79 ug/ml from Yan et al. reference above), the 60% reduction will reach to 716 ng/ml far above than 480 ng/ml. In brief, the current invention provides an improved and more accurate way for one clinician in identifying DIC for better care and subsequent treatment.
Conclusion
No claim is allowed.
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CHANGHWA J. CHEU
Primary Examiner
Art Unit 1678
/CHANGHWA J CHEU/Primary Examiner, Art Unit 1678