DETAILED ACTION
The amendment and RCE filed on 12/03/2008 has been entered and fully considered. Claims 1-4,10-12,14,16-23,25-26,30-32,40-41,43-46 and 51-53 are pending, of which claims 1, 16-17, 19, 22-23, 25, 32 and 40-41, 45 and 51 are amended.
Response to Amendment
In response to amendment, the examiner modifies rejection over the prior art established in the previous Office 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 .
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1-4, 10-12, 14, 17-18, 21-23, 25-26, 30-32, 40-41, 43-46 and 51-53 is/are rejected under 35 U.S.C. 103 as being unpatentable over Parker (US 2011/0236918, IDS) in view of Ochoa-Riva (Food Bioprocess Technol 2017, IDS) (Ochoa-Riva).
Regarding claim 1, Parker teaches a method to perform genetic analysis of a sample of a biological organism (abstract), the method comprising
preparing the sample to obtain a processed sample comprising solubilized proteins (par [0062]);
fractionating the processed sample to obtain a solubilized protein fraction comprising the solubilized proteins from the sample (par [0062]);
digesting the solubilized protein fraction from the sample to obtain digested peptides from the sample (par [0032][0062]);
fractionating the digested peptides to obtain fractionated digested peptides from the digested solubilized protein fraction from the sample (par [0032]); and
detecting a marker genetic variation of the fractionated digested peptides from the sample through proteomic analysis (par [0032][0035]).
While parker teaches solubilizing sample with solvent (par [0062]), Parker does not specifically teach applying to the sample an energy field resulting in an increased thermodynamic or total energy of the sample to obtain a processed sample comprising solubilized proteins. However, Ochoa-Riva teaches that applying to the sample an energy field resulting in an increased thermodynamic or total energy of the sample to obtain a processed sample comprising solubilized proteins, and applying the energy field resulting in increased the yield of solubilized proteins (abstract). It would have been obvious to one of ordinary skill in the art to apply to the sample an energy field resulting in an increased thermodynamic or total energy of the sample to obtain a processed sample comprising the solubilized proteins, in order to increase the yield of solubilized proteins.
Parker teaches that “The powder was collected and treated with 50 mM ammonium bicarbonate containing 1% Protease Max and DTT (30 mM). The sample was centrifuged and separated into supernatant and insoluble hair faction” (par [0062]). Thus, applying an energy field to the sample treated with 50 mM ammonium bicarbonate containing 1% Protease Max and DTT (30 mM) solvent so as to increase the soluble protein in the solvent would not change Parker’s principle of operation.
Claim 1 recites that the method includes a sub-method selected from the group consisting of (i) and (ii). Because this is a Markush group, only one of the listed alternatives needs to be met for purposes of anticipation or obviousness. The prior art (Ochoa-Rivas) teaches sub-method (i), which is sufficient to satisfy claim 1 under the Markush framework.
Regarding claim 2, Parker teaches that wherein the preparing the sample comprises performing cell and tissue disruption (crushing) and performing protein solubilization (par [0049]).
Regarding claim 3, Parker teaches that wherein preparing the sample comprises: performing removal of contaminants and/or performing protein enrichment following performing protein solubilization (par [0049]).
Regarding claim 4, Ochoa-Riva teaches that where the applying is performed by sonication, and applying sonication to a sample can increase the yield of solubilized proteins (abstract). It would have been obvious to one of ordinary skill in the art to apply sonication to the sample in solvent during Parker’s sample preparation process, in order to increase the yield of solubilized proteins.
Regarding claim 10, Parker teaches that wherein the fractionating the processed sample and/or the fractionating the digested peptides is performed by a chromatography technique (par [0032]).
Regarding claim 11, Parker teaches that wherein the digesting is performed enzymatically with one or more site specific proteolytic enzymes (trypsin) (par [0032]).
Regarding claim 12, Parker teaches that wherein the one or more site specific proteolytic enzymes is selected from the group consisting of: trypsin (par [0032]), chymotrypsin, Lys-C, Arg-C, Asp-N, and Glu-C, non-specific; pepsin, and proteinase K.
Regarding claim 14, Parker teaches that wherein the detecting a marker genetic variation of the digested peptides from the sample is performed by mass spectrometry (par [0032]).
Regarding claim 16, Claim 16 depends from claim 1 and adds limitations relating to synthesizing a marker peptide and analyzing it by mass spectrometry to provide a marker mass spectrum. However, claim 1 recites that the method includes a sub-method selected from the group consisting of (i) and (ii). Because this is a Markush group, only one of the listed alternatives needs to be met for purposes of anticipation or obviousness. The prior art (Ochoa-Rivas) teaches sub-method (i), which is sufficient to satisfy claim 1 under the Markush framework.
Accordingly, because sub-method (ii) is optional, the additional features introduced in claim 16 apply only when sub-method (ii) is selected, and thus do not limit the claimed method with respect to the embodiment relying on sub-method (i). As such, the limitation added in claim 16 does not patentably distinguish the claim over the prior art combination of Parker and Ochoa-Rivas, which already renders claim 1 obvious.
Therefore, claim 16 remains obvious over Parker in view of Ochoa-Rivas.
Regarding claim 17, Parker teaches that wherein performing mass spectrometry of a digested peptide of the sample to obtain a detected mass spectrum of each of the digested peptides is performed by tandem mass spectrometry (par [0011] [0032]).
Regarding claim 18, Parker teaches that wherein the marker peptide comprises a plurality of marker peptides each comprising a marker genetic protein variation (polymorphism) (par [0035][0038]).
Regarding claim 21, Parker teaches that wherein the genetic protein variation is a single amino acid polymorphism (SAP), an amino acid deletion and/or an amino acid insertion (Therefore, any strand of hair has the potential, in its intrinsic amino acid sequences, to provide a statistically conclusive link to any given individual) (par [0044]).
Regarding claim 51, Parker teaches a method to perform genetic analysis of a sample of a biological organism (abstract), the method comprising
fractionating the processed sample to obtain a solubilized protein fraction comprising the solubilized proteins from the sample (par [0062]) and a solubilized DNA fraction comprising nuclear and/or mitochondrial genome (a predicted combination of peptide biomarker polymorphisms could be determined using DNA-based methodology, such as SNP microarray chips or polymerase chain reaction, which could then be confirmed using proteomic methodology) (par [0056]);
digesting the solubilized protein fraction from the sample to obtain digested peptides from the sample (par [0032][0062]);
fractionating the digested peptides to obtain fractionated digested peptides from the digested solubilized protein fraction from the sample (par [0032]); and
detecting a marker genetic variation of the fractionated digested peptides from the sample through a comparison (confirm) of proteomic analysis of the solubilized protein fraction and genetic analysis of the solubilized DNA fraction of the sample (par [0056]).
Parker teaches that “Methods and processes for conducting genetic analysis through protein polymorphisms, including identification of individuals, establishment of paternity and measurement of genetic diversity and distance. Some illustrative embodiments of methods of the present invention include the identification of peptide biomarkers using proteomic techniques, including liquid chromatography-tandem mass spectrometry from biological samples, using hair, dentin, or bone as a source of the protein to be analyzed.” (abstract). Here Parker teaches that proteomic analysis of a sample is done by detecting protein polymorphisms. Protein polymorphism is the maker protein of genetic protein variation. Thus, Park teaches detecting a genetic protein variation in the solubilized proteins from the sample by performing a proteomic analysis of the solubilized protein fraction.
Parker also teaches that “in additional embodiments, a predicted combination of peptide biomarker polymorphisms could be determined using DNA-based methodology, such as SNP microarray chips or polymerase chain reaction, which could then be confirmed using proteomic methodology.” (par [0056]). It is well-known that polymerase chain reaction (PCR) is performed with a solubilized DNA of the sample. Thus, Parker teaches detecting a genomic variation of the nuclear and/or mitochondrial genome by performing a genetic analysis of a solubilized DNA fraction of the sample; and
comparing the detected genetic protein variation and/or the detected genomic variation with a marker genetic protein variation and/or of a marker genomic variation respectively validated to be detectable in the sample (which could then be confirmed using proteomic methodology) (par [0056]).
The prior art should be considered as a whole. All embodiments disclosed in the prior art should be considered. In one embodiment Parker teaches producing soluble protein for proteomic analysis. Parker further teaches that “in additional embodiments, a predicted combination of peptide biomarker polymorphisms could be determined using DNA-based methodology, such as SNP microarray chips or polymerase chain reaction, which could then be confirmed using proteomic methodology.” (par [0056]). It is well-known that polymerase chain reaction (PCR) is performed with a solubilized DNA of the sample. Thus, Parker also teaches detecting a genomic variation of the nuclear and/or mitochondrial genome by performing a genetic analysis of a solubilized DNA fraction of the sample, and comparing the detected genetic protein variation and/or the detected genomic variation with a marker genetic protein variation and/or of a marker genomic variation respectively validated to be detectable in the sample (which could then be confirmed using proteomic methodology) in additional embodiments (par [0056]).
Again, while parker teaches solubilizing sample with solvent (par [0062]), Parker does not specifically teach applying to the sample an energy field resulting in an increased thermodynamic or total energy of the sample to obtain a processed sample comprising solubilized proteins. However, Ochoa-Riva teaches applying to the sample an energy field resulting in an increased thermodynamic or total energy of the sample to obtain a processed sample comprising solubilized proteins, and applying an energy field to a sample can increase the yield of solubilized proteins (abstract). It would have been obvious to one of ordinary skill in the art to apply an energy field to the sample in solvent during Parker’s sample solubilizing process, in order to increase the yield of solubilized proteins.
Parker teaches that “The powder was collected and treated with 50 mM ammonium bicarbonate containing 1% Protease Max and DTT (30 mM). The sample was centrifuged and separated into supernatant and insoluble hair faction” (par [0062]). Thus, applying an energy field to the sample treated with 50 mM ammonium bicarbonate containing 1% Protease Max and DTT (30 mM) solvent so as to increase the soluble protein in the solvent would not change Parker’s principle of operation.
A person skilled in the art would have appreciated that if applying an energy field to a sample can increase the solubility of peanut protein, the same energy field to a sample would also increase the solubility of other proteins with reasonable expected success.
A finding of obviousness does not require certainty. See, e.g., In re O'Farrell, 853 F.2d 894, 903-904 (Fed. Cir. 1988) ("Obviousness does not require absolute predictability of success .... all that is required is a reasonable expectation of success."). Further, "obviousness cannot be avoided simply by a showing of some degree of unpredictability in the art so long as there was a reasonable probability of success." Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007).
Regarding claim 22, Parker teaches that wherein a genomic variation of the nuclear and/or mitochondrial genome is detected by performing the genetic analysis of the solubilized DNA fraction par [0056]), the genomic variation is a single nucleotide polymorphism (SNP), a nucleotide deletion and/or a nucleotide insertion (par [0044]).
Regarding claim 23, Parker teaches that wherein a genomic variation of the nuclear and/or mitochondrial genome is detected by performing the genetic analysis of the solubilized DNA fraction (par [0056]), wherein the genomic variation is within the short tandem repeat (STR) regions of the nuclear genome or within the mitochondrial genome (par [0050]).
Regarding claim 26, Parker teaches that wherein the marker genetic protein variation comprises a marker genetic protein variation validated to be detectable in the sample (par [0036]).
Regarding claim 30, Parker teaches that wherein the sample is g single hair sample (par [0046] [0062]).
Regarding claim 31, Parker teaches that wherein the sample is hair, and wherein the marker peptide comprises a validated genetic protein variation of a gene listed in Table 8 of the specification (Table 1).
Regarding claim 32, Parker teaches that wherein the sample is hair, and wherein the marker genetic protein variation comprises one or more genetic protein variations listed in Table 11 of the specification (Table 1).
Regarding claim 40, Parker- Ochoa-Riva discloses a system to perform genetic analysis of a sample of a biological organism (abstract), the system comprising
a reagent configured for preparing the sample upon application of an energy
field to the sample to obtain a processed sample comprising solubilized proteins (Ochoa-Riva, abstract); and/or
a marker peptide comprising a genetic protein variation validated to be detectable in the sample (Parker, par [0036]);
a database validated to be detectable in the sample (Parker, par [0036]);
alone or in combination with other reagents effective to enable performance of the preparing, the digesting (Parker, par [0032]), and/or the detecting recited in the method of claim 1 (Parker, par [0032] [0035][0056]).
Regarding claim 41, Parker discloses that the method further comprising information to access a database comprising information about genetic protein variations (par [0035][0036]).
Regarding claim 43, Parker discloses that wherein the sample is g single hair sample (par [0044]).
Regarding claim 44, Parker discloses that wherein the sample is hair, and wherein the marker peptide comprises a validated genetic protein variation of a gene listed in Table 8 of the specification (Table 1).
Regarding claim 45, Parker discloses that wherein the sample is hair, and wherein the marker genetic protein variation comprises one or more genetic protein variations listed in Table 11 of the specification (Table 1).
Regarding claim 46, Parker discloses wherein the sample is hair, and wherein the marker peptide comprises one or more peptides having sequence SEQ ID NO: 151 to SEQ ID NO: 721 (Table 1).
Regarding claim 52, Ochoa-Riva teaches applying to the sample an energy field resulting in an increased thermodynamic or total energy of the sample to obtain a processed sample comprising solubilized proteins, wherein the applying is performed by applying microwave energy (abstract). Microwave is an electromagnetic energy.
Regarding claim 53, Ochoa-Riva teaches applying to the sample an energy field resulting in an increased thermodynamic or total energy of the sample to obtain a processed sample comprising solubilized proteins, wherein the applying is performed by applying ultrasound energy (abstract). Ultrasound is a form of acoustic energy.
Allowable Subject Matter
Claim 19-20 are allowed.
The following is an examiner’s statement of reasons for allowance: Parker does not teach wherein comparing the mass spectrum of the fractionated digested peptides of the sample with a marker mass spectrum is performed by comparing the mass spectrum of the fractionated digested peptides with a mass spectrum of a protein variant database as recited in claim 19. Claim 20 depends on claim 19.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Claim 25 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter: The prior art of record does not teach or fairly suggest comparing the detected mass spectrum with the marker mass spectrum, to detect the genetic protein variation in the sample.
Response to Arguments
Applicant's arguments filed 11/26/2025 have been fully considered but they are not persuasive.
1. Applicant argues Parker “prepares the sample by grinding between glass” and therefore does not disclose the claimed sample-preparation method.
The Examiner notes that the rejection does not rely on Parker to teach the energy-field solubilization step of claim 51. As explained in the Office Action, Parker is relied upon only for the proteomic/genomic analytical workflow, not for the initial sample-processing technique.
The energy-field solubilization step is taught by Ochoa-Rivas, which describes applying microwave or ultrasound energy to increase the thermodynamic energy of the sample and enhance protein solubilization (e.g., Abstract, “MW-assisted extraction… increased extraction and solubilization of proteins”)
Thus, Parker’s use of grinding does not overcome the §103 rejection, because Parker is not relied on for this limitation.
2. Applicant argues Parker does not teach “fractionating the processed sample into a protein fraction and a DNA fraction.”
This argument is also not persuasive.
(A) Parker teaches processing biological samples to obtain both protein-derived polymorphisms and DNA-derived polymorphisms.
Parker explicitly describes:
identification of peptide polymorphisms through proteomic analysis (e.g., Figs. 1-2; par [0032]-[0035])
obtaining DNA-based genetic variation information (e.g., SNP microarray, PCR analysis) and comparing it to protein polymorphism data:
“…a predicted combination of peptide biomarker polymorphisms could be determined using DNA-based methodology, such as SNP microarray chips or PCR, which could then be confirmed using proteomic methodology.” (par [0056])
Paragraph [0056] makes clear that Parker contemplates performing DNA analysis and proteomic analysis from the same biological sample. The skilled artisan would understand that obtaining both fractions necessarily requires separating (i.e., “fractionating”) the sample into at least a DNA-containing fraction and a protein-containing fraction, whether by conventional extraction, centrifugation, lysis separation, or other routine means.
Fractionation of lysates into protein and DNA components is a well-known, routine step in multi-omic workflows and would have been obvious to a person of ordinary skill.
(B) Claim 51 does not require a specific fractionation method.
Claim 51 merely recites:
“fractionating the processed sample to obtain a solubilized protein fraction… and a solubilized DNA fraction…”
The claim does not recite any particular fractionation mode. Standard cell-lysis and biomolecule separation processes inherently produce separate protein and nucleic acid fractions, and Parker expressly teaches downstream analyses of both peptide polymorphisms and DNA polymorphisms.
Therefore, Parker teaches or suggests this limitation.
3. Applicant argues Parker does not disclose “detecting a marker genetic variation… through comparison of proteomic analysis to genetic analysis.”
This argument is directly contradicted by Parker.
Parker explicitly teaches the comparison required by claim 51:
“…a predicted combination of peptide biomarker polymorphisms could be determined using DNA-based methodology… which could then be confirmed using proteomic methodology.” (par [0056])
This passage teaches precisely what claim 51 recites:
performing genetic analysis on the DNA fraction
performing proteomic analysis on the peptide fraction
detecting genetic variation by comparing the two results
Thus, Parker teaches the very comparison Applicant asserts is missing.
4. Applicant asserts that “none of the art in any combination teaches the unique combination of features claimed.”
This assertion is not persuasive.
Ochoa-Rivas teaches the energy-field solubilization step required by the claim.
Parker teaches all later steps:
obtaining protein-derived peptides
obtaining DNA-based genetic information
fractionation inherent in multi-omics workflows
comparing DNA-predicted polymorphisms with proteomic polymorphisms (par [0056])
Combining Ochoa-Rivas’s improved sample-solubilization with Parker’s multi-omic analysis constitutes a predictable, routine modification yielding no unexpected result.
The motivation to combine arises naturally: Ochoa-Rivas improves the solubilization and extraction of proteins, which is beneficial for the downstream proteomic workflows of Parker.
Accordingly, the combination is proper under KSR.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to XIAOYUN R XU, Ph. D. whose telephone number is (571)270-5560. The examiner can normally be reached M-F 8am-5pm.
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/XIAOYUN R XU, Ph.D./ Primary Examiner, Art Unit 1797