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 .
1. Claims 2-10, 13-16, 19, 22-33, 37, 42, 44-58, and 60 have been cancelled. Claims 1, 12, 17, 18, 34, 38-41, and 59 have been amended.
Claims 1, 11, 12, 17, 18, 20, 21, 34-36, 38-41, 43, and 59 are pending and under examination.
Claim Objections
2. Claim 38 is objected to because of the recitation “a combination thereof” in lines 3-4. Appropriate correction to “the combination thereof” is required.
Claim Rejections - 35 USC § 112(b)
3. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
4. Claim 12 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 12 does not further limit the parent claim 11 because the recitation “the blood sample is additionally contacted with an anticoagulant” is already in the parent claim 11.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
5. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
6. Claims 1, 11, 12, 17, 18, 20, 21, 34-36, 38-41, 43, and 59 are rejected under 35 U.S.C. 103 as being unpatentable over Chomczynski et al. (PGPUB 2006/0147944), in view of all Horlitz et al. (PGPUB 2014/0227687), Mosbah et al. (Transplantation Proceedings, 2006, 38: 1229-1235), and Collins et al. (U.S. Patent No. 4,938,961).
Chomczynski et al. teach a method for stabilizing nucleic acids in a blood sample, the method comprising contacting the blood sample with a stabilizing storage reagent comprising EDTA and low molecular weight PEG 200 (see Abstract; ([0012]-[0014]; [0027]; [0090]). Chomczynski et al. teach that PEG 200 concentration could be 0.1-10% (see [0030]), which overlaps with the claimed range of 2-7%.
In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05.
While Chomczynski et al. do not specifically teach extracellular nucleic acids, Horlitz et al. teach that blood contains extracellular nucleic acids and that the extracellular nucleic acids are useful for non-invasive diagnosis and prognosis; the preservation of extracellular nucleic acid integrity in blood or plasma is crucial for subsequent analysis (see [0002]-[0003]; [0005]; [0011]). Horlitz et al. also teach that dimethylpropanamide is highly efficient in stabilizing the extracellular nucleic acids and the cells present in blood and plasma (by stabilizing the blood cells and reducing the risk of contamination with intracellular nucleic acids) and is useful for enhancing the accuracy and reliability of diagnostic and prognostic tests based on extracellular nucleic acids; Horlitz et al. teach stabilizing blood by using a composition comprising dimethylpropanamide, EDTA, and the pan-caspase inhibitor Q-VD-OPH (i.e., modified caspase-specific peptide), where the concentrations of dimethylpropanamide in the stabilized blood sample is 2.5 or 5% and that of Q-VD-OPH is 1 [Symbol font/0x6D]M (claims 18, 39, 41, and 59) (see [0003]; [0011]-[0023]; [0027]; [9933]; [0067]; [0071]-[0073]; [0079]-[0080]; [0110]; [0283]-[0284]). Based on these teachings, one of skill in the art e, one of skill in the art would have readily recognized that practicing the method of Chomczynski et al. would stabilize all nucleic acids in the blood sample, including the extracellular nucleic acids useful as diagnosis and prognosis tools (claim 1) and also that plasma samples could be used instead of the blood samples (claim 36). One of skill in the art would have found obvious to modify the composition of Chomczynski et al. by further adding dimethylpropanamide and Q-VD-OPH to a final blood concentration of 2.5 or 5% and 1 [Symbol font/0x6D]M, respectively, to achieve the predictable result of obtaining a composition suitable to stabilize the extracellular and intracellular nucleic acids in blood or plasma samples. MPEP 2144.06 [R-6] I states:
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)
By doing so, one of skill in the art would have obtained and used a composition comprising 2.5 or 5% dimethylpropanamide, 1 [Symbol font/0x6D]M Q-VG-OPH, and EDTA (i.e., an anticoagulant) (claims 1, 11, 12, 18, 34, 35, 39-41, and 59). By doing so, one of skill in the art would have also used a stabilization solution without additives promoting cell lysis, cross-linking, or toxicity (claims 21 and 43)
Chomczynski et al. and Horlitz et al. do not teach high molecular weight PEG at the specific concentration ranges disclosed in claims 1 and 12. However, Horlitz et al. teach using cell stabilizers to reduce the release of intracellular nucleic acids (see [0017]; [0028]-[0032]; [0067]). Mosbah et al. teach that high molecular weight PEG (20 or 35 kDa) stabilizes blood cell membranes; Mosbah et al. teach using high molecular weight PEG at a final concentration of 0.3% for blood stabilization, wherein PEG prevents RBCs aggregation and preserves their morphology; Mosbah et al. discloses that PEG is taught by the prior art as a cell membrane stabilizer (see Abstract; p. 1230, Table 1; paragraph bridging p. 1230 and 1231; p. 1231, column 1, first full paragraph; paragraph bridging p. 1233 and 1234; p. 1234, column 1, first full paragraph). Although Mosbah et al. do not specifically disclose water, Collins et al. teach that PEG is soluble in water (see Example 2, paragraph bridging columns 6 and 7). Based on these teachings, one of skill in the art would have reasonably concluded that stabilizing the cells with high molecular weight PEG would further increase the stabilization of extracellular and intracellular nucleic acids. One of skill in the art would have found obvious to modify the stabilizing composition of Chomczynski et al. and Horlitz et al. by further adding high molecular weight PEG dissolved in water in an amount such as to result in a final concentration of 0.3% in the blood sample with the reasonable expectation that doing so would result in a composition providing better stabilization for the extracellular and intracellular nucleic acids in blood samples (claims 1 and 20). Since the prior art teaches that high molecular PEG stabilizes the cell membranes, one of skill in the art would have reasonably expected reduced release of genomic DNA (claim 17). Since Horlitz et al. teach isolation of the extracellular nucleic acids (see [0067]; [0133]-[0137]; [0203]), one of skill in the art would have found obvious to further isolate the extracellular nucleic acids from the blood sample for further analysis. By doing so, one of skill in the art would have obtained a higher yield of extracellular nucleic acids compared to using high molecular PEG alone (claim 1).
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
Response to Arguments
7. The argument that Chomczynski does not teach the combination of low and high molecular weight PEG is not found persuasive because it addresses the reference individually.
The argument that Chomczynski only teaches PEG 200 at concentrations of 50-60% at alkaline pH for the purpose of lysis is not found persuasive because it does not address the basis for rejection. PEG 200 at concentrations of 50-60% at alkaline pH are only used Chomczynski in the processing reagent, not in the stabilizing storage reagent (see Abstract; [0090]-[0091]). As noted in the rejection, Chomczynski teaches that PEG concentration could be 0.1-10%.
For these reasons, the following arguments are not found persuasive: (1) Chomczynski would have discouraged from using low concentrations of PEG for stabilization; and (2) a direct comparison to Chomczynski’s storage reagent would not be meaningful because Chomczynski’s storage reagent is not directed to the preservation of extracellular nucleic acids.
The arguments that Horlitz does not teach PEG and that Chomczynski and Horlitz do not disclose or suggest using high molecular weight PEG are not found persuasive because they do not address the combination of all cited references.
The argument of no motivation to combine is not found persuasive because it is not supported by any evidence.
The argument that that the claimed four-component system is not disclosed or suggested by any reference is not found persuasive because none of the references has to teach every claim limitation.
The argument that combining Chomczynski and Horlitz would require multiple selections from multiple references without any articulated reason or motivation to make the specific selection is not found persuasive. The rejection provides the reason to combine Chomczynski and Horlitz. Furthermore, it is clear from the rejection that combining Chomczynski and Horlitz does not require multiple selections from multiple references.
The argument of synergistic effect between high and low molecular with PEG is not found persuasive. As previously noted, there is no evidence of synergistic or even additive effect.
Example 12 and 16 as well as Fig. 12-13 and 19-20 were previously addressed. With respect to Fig. 16, the data shows that determining the optimal ratio of low and high molecular weight PEG would have only entailed routine experimentation. There is no evidence to the contrary. Importantly, the claimed concentrations of low and high molecular weight PEG are taught by the cited prior art.
8. No claim is allowed. No claim is free of prior art.
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/ILEANA POPA/Primary Examiner, Art Unit 1633
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