3
DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Election/Restrictions
Applicant’s election without traverse of i) nucleic acid to protein cross-linking and (ii) nucleic acid to nucleic acid intra-molecular and/or inter-molecular cross-links, undergoing detection and/or monitoring of a neurodegenerative condition; imidazolidinyl urea; amino Acids, Imine Schiff base, cerebrospinal fluid in the reply filed on 8/26/2025 is acknowledged.
Priority
The instant application was filed 09/27/2023 and is a continuation of 16861150 , filed 04/28/2020, which is a continuation of 13766207 , filed 02/13/2013, and
claims priority from provisional application 61597908 , filed 02/13/2012 and
claims priority from provisional application 61671681 , filed 07/14/2012.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows: Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like)(page 31) in accordance with 37 CFR 1.831(c). There is no sequence listing.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Claim Objections
Claim 29 objected to because of the following informalities:
Claim 29 recites, “urea.:” The colon is not needed and appears to be a typographical error.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
As set forth in In re Alonso 88 USPQ2d 1849 (Fed. Cir. 2008), at 1851:
The written description requirement of 35 U.S.C. § 112, ¶ 1, is straightforward: “The specification shall contain a written description of the invention ….” To satisfy this requirement, the specification must describe the invention in sufficient detail so “that one skilled in the art can clearly conclude that the inventor invented the claimed invention as of the filing date sought.” Lockwood v. Am. Airlines, Inc., 107 F.3d 1565, 1572 [41 USPQ2d 1961] (Fed. Cir. 1997); see also LizardTech, Inc. v. Earth Res. Mapping, Inc., 424 F.3d 1336, 1345 [76 USPQ2d 1724] (Fed. Cir. 2005); Eiselstein v. Frank, 52 F.3d 1035, 1039 [34 USPQ2d 1467] (Fed. Cir. 1995).
Alonso at 1852:
A genus can be described by disclosing: (1) a representative number of species in that genus; or (2) its “relevant identifying characteristics,” such as “complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.” Enzo, 323 F.3d at 964.
Claims 21-37 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.
In applying the test as set forth in Alonso, it is noted that applicant is claiming a method of stabilizing a biological sample for analysis, comprising: obtaining in a sample collection containing a biological sample from a subject, the biological sample comprising circulating cell-free nucleic acids from the subject; admixing the biological sample while within the sample collection container with a protective agent composition to form a mixture of the protective agent composition and the sample, the protective agent composition comprising: at least one preservative, and an anticoagulant, wherein nucleic acids within the sample are suitable for polymerase chain reaction and DNA sequencing.
Thus the claims encompass stabilizing any biological sample for analysis by using at least of anything that can be considered a preservative, anything that can be considered an anticoagulant. Thus the claims encompass a genus of at least one preservative and a genus of an anticoagulant. The claims provide no limitations with respect to the concentration of either the preservative or anticoagulant. Thus the claims further encompass any concentration of preservative and any concentration of anticoagulant which provides for the intended outcome.
Dependent claim 23 draws the invention to the protective agent further comprises a quenching agent, and the method further comprises quenching any free formaldehyde that may be present with the quenching agent from the protective agent composition such that the free formaldehyde reacts to form a reaction product that is inert to the nucleic acids of the biological sample. While claim 24 depends from claim 23 and draws the invention to wherein the sample for at least 7 days after collection in the collection container is substantially devoid of aldehyde induced (i) nucleic acid to protein cross-linking, (ii) nucleic acid to nucleic acid intra-molecular and/or inter- molecular cross-links; or both (i) and (ii). Thus it appears in the absence of a quencher the nucleic acids do not appear to be stabilized from free formaldehyde or crosslinking.
The specification in paragraph 0052 provides possible concentrations of preservative agents.
The specification in paragraph 0052 provides possible concentrations of quenching agents.
. Thus the specification fails to disclose any structure and thus lacks adequate written description of the protective agent claimed that has the functional characteristics claims.
Trezl (Molecular and Cellular Biochemistry (2003) volume 244, pages 167-176) teaches, “ Endogenous formaldehyde had been first determined in human blood (0.4–0.6 µg/ml)in 1983 by our research group [2, 3]. The latest determination of endogenous formaldehyde of human blood plasma is in good agreement with our results [4]”
Further claim 24 require the sample is substantially devoid of aldehyde induced (i) nucleic acid to protein cross-linking, (ii) nucleic acid to nucleic acid intra-molecular and/or inter- molecular cross-links; or both (i) and (ii). The specification while reciting times does not provide any imidazolidinyl urea concentration or imidazolidinyl urea reaction product concentration that specifically have this functional characteristic.
The specification teaches
[0121] FIG. 8a illustrates how conformational damage to DNA can be avoided using the teachings herein. There is depicted fluorescence spectra of native-DNA (control), CF-DNA-BCT (an exemplary protective agent composition within the present teachings) preserved DNA, formaldehyde preserved DNA and glutaraldehyde preserved DNA. The top plot is for a sample held at room temperature for 7 days. The middle plot is for a sample held at room temperature for 7 days and then heated at 60.degree. C. for 1 hr. The lowest plot is for a sample held at room temperature for 7 days and heated at 90.degree. C. for 2 min.
[0122] FIG. 8b further illustrates how conformational damage to DNA can be avoided using the teachings herein. There is depicted fluorescence spectra of native-DNA (control), CF-DNA-BCT (an exemplary protective agent composition within the present teachings) preserved DNA, formaldehyde preserved DNA and glutaraldehyde preserved DNA. The top plot is for a sample held at room temperature for 14 days. The middle plot is for a sample held at room temperature for 14 days and then heated at 60.degree. C. for 1 hr. The lowest plot is for a sample held at room temperature for 14 days and heated at 90.degree. C. for 2 min.
The specification in paragraph 123-127 teach the ability of CF-DNA BCT to allow amplification of nucleic acids. However the specification does not provide any imidazolidinyl urea concentration, EDTA concentration or glycine concentration or imidazolidinyl urea reaction product concentration that specifically have this functional characteristic.
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 21-37 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.
Claim 21 is indefinite because it lacks a positive active step relating back to the preamble. The preamble recites a method stabilizing a biological sample for analysis, however the last positive active step is drawn to admixing the biological sample. Therefore it is unclear as to whether the method is drawn to stabilizing a biological sample for analysis or admixing the biological sample.
Claim 21 recites, “ a method stabilizing a biological sample for analysis.” The recitation suggest there are methods which do not stabilize a biological sample for analysis. The specification and claims provide no standard to differentiated methods which do not stabilize a biological sample for analysis from methods which do not stabilize a biological sample for analysis.
Claim 21 further recites, “wherein nucleic acids within the sample are suitable for polymerase chain reaction and DNA sequencing.” The metes and bounds are unclear if the nucleic acids are suitable for polymerase chain reaction and DNA sequencing is in the biological sample or after the admixing. Further the recitation of nucleic acids suitable for polymerase chain reaction and DNA sequencing suggest there are nucleic acids not suitable for polymerase chain reaction and DNA sequencing. The specification and claims provide no specific standard to differentiate the two. Thus the metes and bounds are unclear what is required of nucleic acids suitable for polymerase chain reaction and DNA sequencing.
Claim 22 recites, “the contacting step.” The claim does not previously recite contacting, nor does the independent claim from which it depends. Thus the metes and bounds are unclear what ”the contacting step” is referencing.
Claim 24 recites, “substantially devoid of aldehyde.” The recitation of “substantially devoid of aldehyde” suggests there are some which are not “substantially devoid of aldehyde.” The specification and claims do not provide a standard or definition to differentiate “substantially devoid of aldehyde” from not “substantially devoid of aldehyde.”
Claim 26 recites, “freshly drawn blood sample.” The recitation of freshly drawn blood sample suggests there is not freshly drawn blood sample. The specification does not provide a standard to differentiate the two.
Claim 31 recites, “the quenching agent comprises a compound that includes at least one functional group capable of reacting with an electron deficient functional group of formaldehyde.” The recitation of functional group capable of reacting with an electron deficient functional group of formaldehyde suggests there are functional group incapable of reacting with an electron deficient functional group of formaldehyde. The specification and claims provide no definition or standard to differentiate an electron deficient functional group of formaldehyde from a functional group incapable of reacting with an electron deficient functional group of formaldehyde
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of pre-AIA 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
Claim(s) 21, 23-28, 31-35, 37 is/are rejected under pre-AIA 35 U.S.C. 102(b) as being anticipated by Fernando (Prenat Diagnose (2010) volume 30, pages 418-424) as evidence by Das ( Acta Histochemica (2013) volume 115, pages 481-486, e-published 12/21/2012).
Attention is directed to MPEP 2129 [R-6], Admissions as Prior Art, which states in part:
I. ADMISSIONS BY APPLICANT CONSTITUTE PRIOR ART
A statement by an applicant >in the specification or made< during prosecution identifying the work of another as “prior art” is an admission **>which can be relied upon for both anticipation and obviousness determinations, regardless of whether the admitted prior art would otherwise qualify as prior art under the statutory categories of 35 U.S.C. 102. Riverwood Int’l Corp. v. R.A. Jones & Co., 324 F.3d 1346, 1354, 66 USPQ2d 1331, 1337 (Fed. Cir. 2003); Constant v. Advanced Micro-Devices Inc., 848 F.2d 1560, 1570, 7 USPQ2d 1057, 1063 (Fed. Cir.1988).
Further, the courts have held information that an applicant admits is in the prior art "may be considered 'prior art' for any purpose, including use as evidence of obviousness under § 103." In re Nomiya, 509 F.2d 566, 570-71 (CCPA 1975).
The instant application in paragraph 00122, 00123, 00124, 00126, 00128, 00129 teaches that CF-DNA BCT is “an exemplary protective agent composition within the teachings.”
`Fernando teaches blood was drawn into Cell-Free DNA BCT (streck catalog, part 218961 or 218962) a vacuum collection tube developed by Streck, Inc., La Vista, NE, that contained proprietary chemicals to stabilize nucleated blood cells. (page 419 bottom 1st column to top of 419 2nd paragraph).
Thus the teachings of Fernando with respect to Cell-Free DNA BCT (streck catalog, part 218961 or 218962) a vacuum collection tube (evacuated to a pressure less than atmosphere) anticipates or renders obvious the instant claims as it is an exemplary protective agent composition within the teachings of the instant application, absent evidence to the contrary. Thus Cell-Free DNA BCT has all the functional characteristics of the dependent claims and must provide for all the ranges of dependent claims in view of the functional limitations of the independent claims.
Das demonstrates that the cell-free DNA-BCT is formaldehyde free (title and introduction).
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 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 negated by the manner in which the invention was made.
Claim 21-35, 36 is/are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Fernando (USPGPUB20100209930) and Fernando (US PGPUB2010/0184069, published July 22, 2010), James (US patent 6,072,086).
Fernando (USPGPUB20100209930) will be referenced in the instant rejection as Fernando A. Fernando (US PGPUB2010/0184069) will be referred to as Fernando B.
Attention is directed to MPEP 2129 [R-6], Admissions as Prior Art, which states in part:
I. ADMISSIONS BY APPLICANT CONSTITUTE PRIOR ART
A statement by an applicant >in the specification or made< during prosecution identifying the work of another as “prior art” is an admission **>which can be relied upon for both anticipation and obviousness determinations, regardless of whether the admitted prior art would otherwise qualify as prior art under the statutory categories of 35 U.S.C. 102. Riverwood Int’l Corp. v. R.A. Jones & Co., 324 F.3d 1346, 1354, 66 USPQ2d 1331, 1337 (Fed. Cir. 2003); Constant v. Advanced Micro-Devices Inc., 848 F.2d 1560, 1570, 7 USPQ2d 1057, 1063 (Fed. Cir.1988).
Further, the courts have held information that an applicant admits is in the prior art "may be considered 'prior art' for any purpose, including use as evidence of obviousness under § 103." In re Nomiya, 509 F.2d 566, 570-71 (CCPA 1975).
The instant application in paragraph 00122, 00123, 00124, 00126, 00128, 00129 teaches that CF-DNA BCT is “an exemplary protective agent composition within the teachings.”
Fernando A teaches, “[0002] This invention relates to the identification and isolation of cell-free nucleic acids in blood samples.”
Fernando A teaches, “Given that the blood of most healthy individuals ordinarily does not contain substantial amounts of cell-free RNA, elevated amounts of cell-free nucleic acids are usually indicative of a health issue (or pregnancy, as fetal cell-free nucleic acids have been identified in maternal blood). Specifically, elevated presence of cell-free mRNA has been found to indicate the existence of various cancers thereby providing support for the belief that these nucleic acids may originate from tumor cells. Consequently, the identification of cell-free RNA within a blood sample could provide insight into the presence and severity of cancer or some other condition.”(0003) Fernando A teaches, “ The contacting step may take place in a blood collection tube into which the blood sample is drawn.”(0013) Fernando A teaches, “The present invention addresses the need for an efficient and consistent method of preserving and testing of a blood sample for elevated levels of cell-free RNA in plasma of the blood sample, which unexpectedly and surprisingly results in short term inhibition of metabolism (i.e., RNA synthesis); long term fixing of blood cells of the blood sample to prevent leaking of cellular RNA into the plasma; fixing the cellular RNA that is within the blood cells to freeze (e.g., immobilize) the protein expression pattern of the blood cells; and stabilizing and protecting the RNA that is in the plasma from nucleases and proteases.”(0008)
Fernando A teaches, “The present invention contemplates a screening method for the identification of a disease state, comprising the steps of: contacting a drawn blood sample that includes a plurality of blood cells with a plasma RNA (e.g., mRNA) protective agent; isolating cell-free RNA from the blood sample; and analyzing (e.g., by quantity, quality, or both) the isolated RNA for the presence, absence, or severity of a disease state. The protective agent may be present in an amount and for a time sufficient so that the RNA synthesis is inhibited for at least two hours. The protective agent may be present in an amount so that blood cells of the drawn blood sample are fixed to substantially prevent leaking of cellular RNA into the plasma. The protective agent may be present in an amount so that any cellular RNA that is within the blood cells at the time of the blood draw is substantially preserved to immobilize the protein expression pattern of the blood cells so that the protein expression pattern of the cells remains substantially the same as at the time of the blood draw. The protective agent may be present in an amount so that the RNA that is in the plasma is substantially stabilized against degradation mediated by the combined action of nucleases and proteases.”(0009)
Fernando A teaches the use of water as a solvent (0029).
Fernando A teaches, “The protective agent may include one or more preservative agents, one or more enzyme inhibitors, one or more metabolic inhibitors, or any combination thereof. The one or more preservative agents may include a formaldehyde releaser such as one selected from the group consisting of: diazolidinyl urea, imidazolidinyl urea, dimethoylol-5,5-dimethylhydantoin, dimethylol urea, 2-bromo-2.-nitropropane-1,3-diol, oxazolidines, sodium hydroxymethyl glycinate, 5-hydroxymethoxymethyl-1-1aza-3,7-dioxabicyclo [3.3.0]octane, 5-hydroxymethyl-1-1aza-3,7dioxabicyclo[3.3.0]octane, 5-hydroxypoly[methyleneoxy]methyl-1-1aza-3,7dioxabicyclo[3.3.0]octane, quaternary adamantine and any combination thereof. The one or more enzyme inhibitors may be selected from the group consisting of: diethyl pyrocarbonate, ethanol, aurintricarboxylic acid (ATA), glyceraldehydes, sodium fluoride, ethylenediamine tetraacetic acid (EDTA), formamide, vanadyl-ribonucleoside complexes, macaloid, heparin, hydroxylamine-oxygen-cupric ion, bentonite, ammonium sulfate, dithiothreitol (DTT), beta-mercaptoethanol, cysteine, dithioerythritol, tris(2-carboxyethyl)phosphene hydrochloride, a divalent cation such as Mg.sup.+2, Mn.sup.+2, Zn.sup.+2, Fe.sup.+2, Ca.sup.+2, Cu.sup.+2 and any combination thereof. The one or more metabolic inhibitors may be selected from the group consisting of: glyceraldehyde, dihydroxyacetone phosphate, glyceraldehyde 3-phosphate, 1,3-bisphosphoglycerate, 3-phosphoglycerate, 2-phosphoglycerate, phosphoenolpyruvate, pyruvate and glycerate dihydroxyacetate, sodium fluoride, K.sub.2C.sub.2O.sub.4 and any combination thereof.” (0010)
Fernando A further teaches, “The contacting step may take place in a blood collection tube into which the blood sample is drawn. The contacting step may take place as the blood sample is drawn. The contacting step may be sufficient so that after a period of at least 7 days from the time the blood sample is drawn, the amount of cell-free RNA present in the blood sample is at least about 90%, at least about 95%, or about 100% of the amount of cell-free RNA present in the blood sample at the time the blood sample is drawn. The contacting step may be sufficient so that after a period of at least about 7 days from the time the blood sample is drawn, the concentration of cell-free RNA relative to the total nucleic acid in the blood sample that is present is at least about 10 times, at least about 20 times, or at least about 50 times the amount of cell-free RNA that would be present in the absence of the contacting step.” (0013)
With regards to claim 21, Fernando A teaches adding a blood sample to a blood collection device containing imidazolidinyl urea which reacts with blood producing reaction products. Fernando A teaches the method is for preservation of cell free nucleic acids in the blood. Blood has nucleated blood cells.
Fernando A does not specifically teach the use of imidazolidinyl urea composition containing glycine and EDTA.
However, Fernando B teaches , “An example of a commercially available tube in accordance with the present teachings is sold under the name Cell-Free DNA BCT by Streck, Inc., Omaha, Nebr.”(0050)
Fernando B teaches, “A method for preserving and processing fetal nucleic acids located within maternal plasma is disclosed, wherein a sample of maternal blood containing fetal nucleic acids is treated to reduce both cell lysis of the maternal blood cells and deoxyribonuclease (DNase) and ribonuclease (RNase) activity within the fetal nucleic acids. The treatment of the sample aids in increasing the amount of fetal nucleic acids that can be identified and tested while maintaining the structure and integrity of the fetal nucleic acids. “ (abstract)
Fernando B teaches, “The protective agent may include roughly about 6 parts by weight IDU per about 1 part by weight EDTA, and roughly about 10 parts by weight IDU per about 1 part glycine.”(0050) Fernando B further teaches, “The amount of active ingredient or fixative (e.g. the formaldehyde releaser) relative to the amount of EDTA may be about 1 to about 10 parts (more preferably about 2 to about 8 parts) by weight of fixative to about 1 part by weight EDTA. The amount of protective agent within a tube prior to blood draw may be about 0.05 to about 1.0 ml and more preferably about 0.1 to about 0.3 ml.” Fernando B teaches, “The following illustrates how a blood collection device in accordance with the present teachings can preserve fetal cell-free DNA and help minimize the cell-free DNA background in maternal plasma at ambient temperature. As will be seen, blood samples are drawn from healthy pregnant donors into (i) standard K.sub.3EDTA (sold under the name BD Vacutainer.RTM. by Becton Dickinson of Franklin Lakes, N.J.) blood collection tubes and (ii) blood collection tubes containing the protective agent taught herein ("the protective agent of the present teachings"), and kept at ambient temperature. For example, the protective agent of the present teachings may include about 500 g/L IDU, about 81 g/L Tripotassium EDTA, and about 47 g/l glycine.” (0050) The glycine of Fernando B is the quenching agent of the instant application.
Fernando B teaches, “The protective agent may comprise an active agent in solution. Suitable solvents include water, saline, dimethylsulfoxide, alcohol and mixtures thereof. The protective agent may comprise diazolidinyl urea (DU) and/or imidazolidinyl urea (IDU) in a buffered salt solution. The protective agent may further comprise EDTA and 2-aminoacetic acid. Alternatively, the protective agent may contain only a fixative (e.g., an active ingredient) and may be free of any additional additives. The amount of any active ingredient within the protective agent may generally be about 10% to about 90% by weight. The active ingredient or fixative may comprise about 70% to about 90% by weight of the protective agent. The protective agent may further contain an anticoagulant such as about 5% to about 20% by weight EDTA. The protective agent may contain about 10% by weight EDTA. The protective agent may include from about 1% to about 40% by weight of nuclease inhibitor. The amount of active ingredient or fixative (e.g. the formaldehyde releaser) relative to the amount of EDTA may be about 1 to about 10 parts (more preferably about 2 to about 8 parts) by weight of fixative to about 1 part by weight EDTA. The amount of protective agent within a tube prior to blood draw may be about 0.05 to about 1.0 ml and more preferably about 0.1 to about 0.3 ml.” (0035) Fernando teaches the about 0.2 ml of protective agent is added to 10 ml of blood.
Fernando B teaches the use of glycine in the solution. Glycine is an amino acid and has a functional group that will react with the electron deficient functional group of the aldehyde. Fernando B teaches the use of water as a solvent (0035)
Fernando B teaches IDU is a formaldehyde releaser (0015, 0031).
James teaches, “The present invention achieves all of the foregoing objects and
solves the problems associated with over-fixation of cell and tissue specimens. Those
problems include the formation of undesired methylene crosslinkages and the loss of
antigenic activity. The present invention solves these problems by providing methods
and compositions for controlling formaldehyde fixation of a biological sample by
quenching the fixative with a formaldehyde-reactive agent.” James teaches, “However,
side-chain modifications and crosslinkages in the tissue can interfere with the capacity
of an analyte to form these noncovalent bonds with an antibody or nucleic acid probe.
Thus, it can be seen that formaldehyde modifications of the sulfhydryl and charged
amino side chains that are involved in specific noncovalent binding interactions with the
applied ligand, are deleterious to assay sensitivity.” James teaches, “However, side-
chain modifications and crosslinkages in the tissue can interfere with the capacity of an
analyte to form these noncovalent bonds with an antibody or nucleic acid probe. Thus, it
can be seen that formaldehyde modifications of the sulfhydryl and charged amino side
chains that are involved in specific noncovalent binding interactions with the applied
ligand, are deleterious to assay sensitivity.” James teaches, “Examples of other
formaldehyde-reactive agents which can be incorporated in accordance with the present
invention are amino acids such as glycine and derivatives thereof such as glycine, ethyl
ester hydrochloride, alanine, asparagine, etc.; proteins such as collagen, gelatin, casein, etc.
As stated in the MPEP, 2144.05 II, “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)."
Therefore it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to cell free DNA BCT reagent preservative reagent by Streck taught by Fernando B in the method of Fernando A and invert the samples tubes to mix and/or optimize the concentrations of IDU, EDTA , glycine and water, for analysis of blood from subjects with cancer . The artisan would be motivated to use a reagent known to preserve nucleic acids including DNA in a sample so they can be detected by antibodies and nucleic acids by PCR and/or sequencing without centrifuging. The artisan would be motivated to mix the tube by inversion as a method of mixing to insure the protective agent is dispersed through the blood sample. The artisan would have a reasonable expectation of success as the artisan is merely optimizing known reagents. (claims 21, 27-35)
With regards to claim 24, Fernando B teaches, “FIG. 8 shows that fetal cell-free DNA percentage stays substantially constant for up to 14 days and provides evidence that the protective agent of the present teachings can protect the integrity of fetal cell-free DNA at ambient temperature for up to 14 days.”
, Fernando A further teaches, “The contacting step may take place in a blood collection tube into which the blood sample is drawn.”(0013).
With regards to claim 26, Fernando A teaches, “0033] The protective agent can be located within a specialized device, wherein the protective agent is already present in the device prior to addition of the blood sample, such as that disclosed in U.S. Patent Publication No. 2004/0137417, incorporated by reference herein. More preferably, the device is an evacuated collection container, usually a tube.”
Further with regards to claim 26, Fernando A teaches, “For example, contacting may be commenced substantially contemporaneously from the time of blood draw (e.g., within less than about 10 minutes of the blood draw) and it may last until nucleic acids are isolated, screened, and/or tested. The contacting step may also be employed to provide a sample with a longer shelf life. Thus, it is possible that a lapse of time of at least about 2 hours, more preferably at least about 6 hours, at least about 24 hours, at least about 7 days or even at least about 14 days can elapse between the time of blood draw (which may be substantially contemporaneous with the contacting step), and the time of any testing or screening of the sample, and or isolation of the nucleic acids.(0028).
The specification on page 15 teaches the quenching agent can be spermidine.
Fernando B teaches IDU is a formaldehyde releaser (0015, 0031).
Thus the presence of a formaldehyde releaser and glycine would produce the reaction products.
Fernando B teaches, “FIG. 8 shows that fetal cell-free DNA percentage stays substantially constant for up to 14 days and provides evidence that the protective agent of the present teachings can protect the integrity of fetal cell-free DNA at ambient temperature for up to 14 days.”
Fernando A teaches no protein-DNA crosslinking (0011)
Further Fernando A teaches, “After contacting the blood sample with the protective agent, the sample may be centrifuged to separate the plasma.”(0039).
Fernando B teaches,” the protective agent may include roughly about 6 parts by weight IDU per about 1 part by weight EDTA, and roughly about 10 parts by weight IDU per about 1 part glycine.”(0050)
Fernando B teaches 0.2 ml of protective reagent which is 200 microliters (paragraph 0031)
Claim 36 rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Fernando (USPGPUB20100209930) and Fernando (US PGPUB2010/0184069, published July 22, 2010), James (US patent 6,072,086) as applied to claim 21-35, 36 above, and further in view of Molina (WO 2012028746).
The teachings of Fernando A and Fernando B, and James are set forth above.
While Fernando A and Fernando B, and James teach cell free DNA from blood or plasma they do not specifically teach CSF.
However, Molina teaches, “The present invention is directed to an in vitro method of detecting cell free nucleic acids, preferably cell free DNA (cfDNA) in a body fluid sample from an individual or a patient, wherein the method comprises the step of accurately and sensitively determining the concentration of cell free nucleic acid in the sample and/or determining the concentration or amount of said cell free nucleic acid of a size range and/or the index of integrity or size fraction ratio (SFR) of said cell free nucleic acid and/or the determination of the presence of genetic polymorphisms (such as known Single Nucleotide Polymorphisms (SNPs) or mutations). The invention encompasses also a method to discriminate body fluid individuals where cfDNA are highly released by comparing the size profile obtained for at least one of three size ranges of cfDNA. The invention also encompasses a method for analysing cell free nucleic acids in individuals for the diagnosis, prognosis or for assessing the evolution of a physiological state, such as the progression of a tumor or metastatic cancer, for monitoring the efficacy of a cancer treatment in a patient or for theragnostic purposes implementing the analysis of these biomarkers.” Molina teaches, “By body fluid sample, it is intended and preferred to designate the body fluids selected from the group consisting of whole blood, serum, plasma, urine, sputum, colonic effluent, bone marrow, lymph, cerebrospinal fluid, lacrymal fluid, sweat, milk, faeces, bronchial lavages and ascites.”
Therefore it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to stabilize nucleic acids from bodily fluids including whole blood, serum, plasma, urine, sputum, colonic effluent, bone marrow, lymph, cerebrospinal fluid, lacrymal fluid, sweat, milk, faeces, bronchial lavages and ascites. The artisan would be motivated to examine whole blood, serum, plasma, urine, sputum, colonic effluent, bone marrow, lymph, cerebrospinal fluid, lacrymal fluid, sweat, milk, faeces, bronchial lavages and ascites to determine if this allows for detection of mutations, cancer and disease as taught by Fernando A and Fernando B and Miolina.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 21-37 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 10981984. Although the claims at issue are not identical, they are not patentably distinct from each other because they are coextensive in scope.
The instant claims are drawn to a method of stabilizing a biological sample for analysis, comprising: obtaining in a sample collection containing a biological sample from a subject, the biological sample comprising circulating cell-free nucleic acids from the subject; admixing the biological sample while within the sample collection container with a protective agent composition to form a mixture of the protective agent composition and the sample, the protective agent composition comprising: at least one preservative, and an anticoagulant, wherein nucleic acids within the sample are suitable for polymerase chain reaction and DNA sequencing.
Claim of 984 are drawn to A method for blood sample treatment comprising: locating about 50 μl to about 400 μl of a protective agent into a tube, the protective agent including imidazolidinyl urea, EDTA and glycine; drawing a blood sample having a first circulating tumor cell concentration into the tube, whereby it contacts the protective agent; isolating circulating tumor cells from the contacted blood sample at least 24 hours after the blood draw, the contacted blood sample having a second circulating tumor cell concentration, wherein the second circulating tumor cell concentration is not lower or higher than the first circulating tumor cell concentration by any statistically significant value; and wherein the concentration of the imidazolidinyl urea after the contacting step is greater than 5 mg/ml; wherein the concentration of the glycine after the contacting step is below about 0.03 g/ml; wherein the protective agent is present in an amount that is less than about 5% of an overall mixture volume of the protective agent and the drawn blood sample; wherein the method is free of any step of refrigerating the contacted blood sample to a temperature below room temperature after it has been contacted with the protective agent composition; and wherein as a result of metabolic inhibition of the circulating tumor cells in the treated blood sample, apoptotic and necrotic pathways are inhibited and the circulating tumor cells are protected from cell degradation.
Thus it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made the claims of 984 are a species encompassed by the instant claims.
Dependent claims are coextensive in scope and/or obvious over the claims of the instant application and/or art cited above.
Claims 21-37 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 10674721. Although the claims at issue are not identical, they are not patentably distinct from each other because they are coextensive in scope.
The instant claims are drawn to a method of stabilizing a biological sample for analysis, comprising: obtaining in a sample collection containing a biological sample from a subject, the biological sample comprising circulating cell-free nucleic acids from the subject; admixing the biological sample while within the sample collection container with a protective agent composition to form a mixture of the protective agent composition and the sample, the protective agent composition comprising: at least one preservative, and an anticoagulant, wherein nucleic acids within the sample are suitable for polymerase chain reaction and DNA sequencing.
Claim of 721 are drawn to A method for blood sample treatment comprising: locating a protective agent into a tube, the protective agent including imidazolidinyl urea (“IDU”), glycince, and EDTA; drawing the blood sample having a first circulating tumor cell concentration into the tube, whereby the blood sample contacts the protective agent; isolating circulating tumor cells from the blood sample after the blood draw, the contacted blood sample having a second circulating tumor cell concentration, wherein the second circulating tumor cell concentration is not lower or higher than the first circulating tumor cell concentration by any statistically significant value; and wherein a concentration of the IDU prior to the contacting step is between about 0.1 g/mL and about 3 g/mL; wherein a concentration of the protective agent after the contacting step is less than about 0.8 g/mL; and wherein a concentration of the glycine after the contacting step is below about 0.03 g/mL..
Thus it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made the claims of 721 are a species encompassed by the instant claims.
Dependent claims are coextensive in scope and/or obvious over the claims of the instant application and/or art cited above.
Claims 21-37 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11634747. Although the claims at issue are not identical, they are not patentably distinct from each other because they are coextensive in scope.
The instant claims are drawn to a method of stabilizing a biological sample for analysis, comprising: obtaining in a sample collection containing a biological sample from a subject, the biological sample comprising circulating cell-free nucleic acids from the subject; admixing the biological sample while within the sample collection container with a protective agent composition to form a mixture of the protective agent composition and the sample, the protective agent composition comprising: at least one preservative, and an anticoagulant, wherein nucleic acids within the sample are suitable for polymerase chain reaction and DNA sequencing.
Claim of 747 are drawn to A method for stabilizing, storing, isolating and analyzing cell-free fetal nucleic acid comprising: drawing a blood sample including a plasma containing donor cellular nucleic acid and cell-free nucleic acid including cell-free fetal nucleic acid directly into an evacuated blood collection tube containing about 0.05 ml to 1.0 ml of a protective agent wherein the protective agent is a solution formed from ingredients including: a) 0.1 to 3 g/ml of imidazolidinyl urea; b) glycine; and c) EDTA; wherein an amount of imidazolidinyl urea relative to an amount of glycine is 10 parts by weight of imidazolidinyl urea to 1 part by weight glycine; storing the blood sample including the plasma for 1 to 14 days, separating the plasma from the blood sample; isolating the cell-free nucleic acid-from the plasma of the stabilized blood sample; and analyzing at least the cell-free fetal nucleic acid isolated from the plasma of the stabilized blood sample; wherein the blood sample and the plasma is not frozen prior to the step of isolating...
Thus it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made the claims of 747 are a species encompassed by the instant claims.
Dependent claims are coextensive in scope and/or obvious over the claims of the instant application and/or art cited above.
Claims 21-37 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 9657227. Although the claims at issue are not identical, they are not patentably distinct from each other because they are coextensive in scope.
The instant claims are drawn to a method of stabilizing a biological sample for analysis, comprising: obtaining in a sample collection containing a biological sample from a subject, the biological sample comprising circulating cell-free nucleic acids from the subject; admixing the biological sample while within the sample collection container with a protective agent composition to form a mixture of the protective agent composition and the sample, the protective agent composition comprising: at least one preservative, and an anticoagulant, wherein nucleic acids within the sample are suitable for polymerase chain reaction and DNA sequencing.
Claim of 227 are drawn to A direct blood draw tube for stabilization of cell-free nucleic acid within a plasma sample comprising: a composition including: a) one or more preservative agents including imidazolidinyl urea; b) one or more enzyme inhibitors; and c) one or more solvents; and wherein the one or more enzyme inhibitors are selected from the group consisting of EDTA, aurintricarboxylic acid, and combinations thereof; wherein an amount of the one or more preservative agents relative to an amount of the one or more enzyme inhibitors is about 3 to about 6 parts by weight of preservative agent to about 2 parts by weight of enzyme inhibitors; wherein the composition contains less than, or about 30% by weight of the one or more enzyme inhibitors; wherein the composition includes some formaldehyde but less than 500 parts per million of formaldehyde; and wherein a concentration of the preservative agent is less than, or about 1000 g/l of the composition; and wherein the direct blood draw tube including the composition and a blood sample located therein is storable at room temperature...
Thus it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made the claims of 227 are a species of product encompassed by the instant claims.
Dependent claims are coextensive in scope and/or obvious over the claims of the instant application and/or art cited above.
Claims 21-37 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 9657227. Although the claims at issue are not identical, they are not patentably distinct from each other because they are coextensive in scope.
The instant claims are drawn to a method of stabilizing a biological sample for analysis, comprising: obtaining in a sample collection containing a biological sample from a subject, the biological sample comprising circulating cell-free nucleic acids from the subject; admixing the biological sample while within the sample collection container with a protective agent composition to form a mixture of the protective agent composition and the sample, the protective agent composition comprising: at least one preservative, and an anticoagulant, wherein nucleic acids within the sample are suitable for polymerase chain reaction and DNA sequencing.
Claim of 227 are drawn to A direct blood draw tube for stabilization of cell-free nucleic acid within a plasma sample comprising: a composition including: a) one or more preservative agents including imidazolidinyl urea; b) one or more enzyme inhibitors; and c) one or more solvents; and wherein the one or more enzyme inhibitors are selected from the group consisting of EDTA, aurintricarboxylic acid, and combinations thereof; wherein an amount of the one or more preservative agents relative to an amount of the one or more enzyme inhibitors is about 3 to about 6 parts by weight of preservative agent to about 2 parts by weight of enzyme inhibitors; wherein the composition contains less than, or about 30% by weight of the one or more enzyme inhibitors; wherein the composition includes some formaldehyde but less than 500 parts per million of formaldehyde; and wherein a concentration of the preservative agent is less than, or about 1000 g/l of the composition; and wherein the direct blood draw tube including the composition and a blood sample located therein is storable at room temperature...
Thus it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made the claims of 227 are a species of product encompassed by the instant claims.
Dependent claims are coextensive in scope and/or obvious over the claims of the instant application and/or art cited above.
Claims 21-37 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-107 of U.S. Patent No. 9926590. Although the claims at issue are not identical, they are not patentably distinct from each other because they are coextensive in scope.
The instant claims are drawn to a method of stabilizing a biological sample for analysis, comprising: obtaining in a sample collection containing a biological sample from a subject, the biological sample comprising circulating cell-free nucleic acids from the subject; admixing the biological sample while within the sample collection container with a protective agent composition to form a mixture of the protective agent composition and the sample, the protective agent composition comprising: at least one preservative, and an anticoagulant, wherein nucleic acids within the sample are suitable for polymerase chain reaction and DNA sequencing.
Claim of 590 are drawn A direct blood draw tube comprising: a composition formulated for stabilizing cell-free nucleic acids within a blood sample including: a) one or more formaldehyde releaser preservative agents; b) ethylenediaminetetraacetic acid (EDTA); c) one or more solvents; d) about 1% formaldehyde; wherein the composition is free of separately added formaldehyde but contains the formaldehyde as a result of the one or more formaldehyde releaser preservative agents; wherein an amount of composition within the direct blood draw tube prior to blood draw is less than, or about 1000 g/liter and is in an amount sufficiently small so that any consequential dilution of the blood sample is avoided; and wherein the direct blood draw tube including the composition: facilitates storage of the blood sample collected in the direct draw blood tube at room temperature for at least, or about 14 days without cell lysis and without cell-free nucleic acid degradation of the blood sample due to DNase and RNase activity after blood draw....
Thus it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made the claims of 590 are a species of product encompassed by the instant claims.
Dependent claims are coextensive in scope and/or obvious over the claims of the instant application and/or art cited above.
Claims 21-37 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 10294513. Although the claims at issue are not identical, they are not patentably distinct from each other because they are coextensive in scope.
The instant claims are drawn to a method of stabilizing a biological sample for analysis, comprising: obtaining in a sample collection containing a biological sample from a subject, the biological sample comprising circulating cell-free nucleic acids from the subject; admixing the biological sample while within the sample collection container with a protective agent composition to form a mixture of the protective agent composition and the sample, the protective agent composition comprising: at least one preservative, and an anticoagulant, wherein nucleic acids within the sample are suitable for polymerase chain reaction and DNA sequencing.
Claim of 513 are drawn A direct blood draw tube comprising: a composition formulated for stabilizing a direct drawn blood sample having cell-free nucleic acids within plasma of the blood sample while the blood sample is in the tube including: a) at least two formaldehyde releaser preservative agents; b) ethylenediaminetetraacetic acid (EDTA); c) one or more solvents; d) less than, or about, 1% formaldehyde as a result of the at least two formaldehyde releaser preservative agents; wherein an amount of the at least two formaldehyde releaser preservative agents within the direct blood draw tube prior to blood draw is an amount of about 50 to about 500 grams per liter; wherein an amount of the composition is in an amount so that any consequential dilution of the blood sample is substantially avoided, and cell-free nucleic acids in the blood sample are not materially diluted; and wherein at least, or about, 7 days elapses between a time of blood draw and a time of any testing or screening of a drawn blood sample, and or isolation of the cell-free nucleic acids.
Thus it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made the claims of 513 are a species of product encompassed by the instant claims.
Dependent claims are coextensive in scope and/or obvious over the claims of the instant application and/or art cited above.
Claims 21-37 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10689686. Although the claims at issue are not identical, they are not patentably distinct from each other because they are coextensive in scope.
The instant claims are drawn to a method of stabilizing a biological sample for analysis, comprising: obtaining in a sample collection containing a biological sample from a subject, the biological sample comprising circulating cell-free nucleic acids from the subject; admixing the biological sample while within the sample collection container with a protective agent composition to form a mixture of the protective agent composition and the sample, the protective agent composition comprising: at least one preservative, and an anticoagulant, wherein nucleic acids within the sample are suitable for polymerase chain reaction and DNA sequencing.
Claim of 686 are A method comprising: preparing a blood collection tube including at least, or about, 200 grams per liter of a composition formulated for stabilizing cell-free nucleic acids within a blood sample, the composition including: a. from about 0.5% to about 20% by weight of a single nuclease inhibitor; b. from about 50 to about 500 grams per liter of one or more formaldehyde releaser preservative agents; and c. one or more solvents; wherein the presence of the one or more formaldehyde releaser preservative agents results in release of at least some formaldehyde and up to, or about, 1% formaldehyde into the composition; and sending the blood collection tube and composition located therein to a remote location for collection of a blood sample that contains cell-free nucleic acids that are stabilized by the composition.
Thus it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made the claims of 686 are a species of product encompassed by the instant claims.
Dependent claims are coextensive in scope and/or obvious over the claims of the instant application and/or art cited above.
Claims 21-37 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11716025. Although the claims at issue are not identical, they are not patentably distinct from each other because they are coextensive in scope.
The instant claims are drawn to a method of stabilizing a biological sample for analysis, comprising: obtaining in a sample collection containing a biological sample from a subject, the biological sample comprising circulating cell-free nucleic acids from the subject; admixing the biological sample while within the sample collection container with a protective agent composition to form a mixture of the protective agent composition and the sample, the protective agent composition comprising: at least one preservative, and an anticoagulant, wherein nucleic acids within the sample are suitable for polymerase chain reaction and DNA sequencing.
Claim of 025 are . A composition for the stabilization of nucleic acids within a plasma sample comprising: a. an amount of free formaldehyde; b. about 200 to 500 g/L of one or more preservative agents including diazolidinyl urea; c. a solvent including water; wherein upon mixing the composition with a blood sample and storing the blood sample at room temperature for at least 7 days, cell-free RNA detection is improved due to reduced cellular RNA presence and a reduction in a decrease in cell-free RNA as a result of the composition..
Thus it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made the claims of 025 are a species of product encompassed by the instant claims.
Dependent claims are coextensive in scope and/or obvious over the claims of the instant application and/or art cited above.
Claims 21-37 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10966421. Although the claims at issue are not identical, they are not patentably distinct from each other because they are coextensive in scope.
The instant claims are drawn to a method of stabilizing a biological sample for analysis, comprising: obtaining in a sample collection containing a biological sample from a subject, the biological sample comprising circulating cell-free nucleic acids from the subject; admixing the biological sample while within the sample collection container with a protective agent composition to form a mixture of the protective agent composition and the sample, the protective agent composition comprising: at least one preservative, and an anticoagulant, wherein nucleic acids within the sample are suitable for polymerase chain reaction and DNA sequencing.
Claim of 421 are A method for collecting mammalian blood cells, comprising steps of: (a) providing a tube including preloaded compounds consisting of (i) ethylene diamine tetra acetic acid (EDTA) and (ii) diazolidinyl urea, the tube having an open end and a closed end that receives cells collected directly from a blood draw and wherein a majority of an interior portion of the tube is substantially free of contact with the preloaded components; (b) drawing a blood sample containing a plurality of blood cells into the tube whereby it contacts the preloaded compounds to yield a final composition, wherein a ratio of a volume of the preloaded compounds to a combined volume of the blood sample and the preloaded compounds is from about 1:100 to about 2:100, and so that the plurality of blood cells of the blood sample are stabilized directly and immediately upon the blood draw; and (c) transporting the blood sample, wherein the blood sample is drawn and transported in the same tube with no processing steps between the blood draw and transporting..
Thus it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made the claims of 025 are a species of product encompassed by the instant claims.
Dependent claims are coextensive in scope and/or obvious over the claims of the instant application and/or art cited above.
Claims 21-37 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11647743. Although the claims at issue are not identical, they are not patentably distinct from each other because they are coextensive in scope.
The instant claims are drawn to a method of stabilizing a biological sample for analysis, comprising: obtaining in a sample collection containing a biological sample from a subject, the biological sample comprising circulating cell-free nucleic acids from the subject; admixing the biological sample while within the sample collection container with a protective agent composition to form a mixture of the protective agent composition and the sample, the protective agent composition comprising: at least one preservative, and an anticoagulant, wherein nucleic acids within the sample are suitable for polymerase chain reaction and DNA sequencing.
Claim of 743 are A method comprising: a) providing a device including: i) a tube having an open end and a closed end, a closure inserted in the open end of the tube, and a vacuum drawn to a predetermined level inside the tube; and ii) preloaded compounds loaded into an interior portion of the tube prior to insertion of the closure and the vacuum draw, such that in an upright position the majority of the interior portion of the tube is substantially free of contact with the preloaded compounds, wherein the preloaded compounds include diazolidinyl urea and/or imidazolidinyl urea, and ethylenediamine tetraacetic acid (EDTA); b) drawing a blood sample into the tube such that the blood sample contacts the preloaded compounds to yield a final composition, wherein a ratio of a volume of the preloaded compounds to a volume of the final composition is from about 1:100 to about 2:100; c) transporting, at ambient temperature, the device including the blood sample to an analysis site; d) puncturing the closure, wherein the puncturing takes place at least three days after the blood sample draw; e) handling the blood sample in a low-toxicity environment wherein the preloaded compounds have an inhalation toxicity amount of zero; and f) transferring at least a portion of the blood sample from the device to another substrate and analyzing cells and cellular components present in the transferred blood sample for disease diagnosis; and wherein the preloaded compounds prevent in vitro cell clumping of the cells in the blood sample; and wherein the method is free of diluting the final composition...
Thus it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made the claims of 743 are a species of product encompassed by the instant claims.
Dependent claims are coextensive in scope and/or obvious over the claims of the instant application and/or art cited above.
Summary
No claims are allowed.
Conclusion
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/Steven Pohnert/Primary Examiner, Art Unit 1683
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