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 .
Detailed Action
This application is a continuation of US application 16/650598, now US patent 11725200, filed March 25, 2020, which is a national stage application of PCT/EP2017/074490, filed September 27, 2017. Claims 1-18, 20, and 22-24 are pending in this application and examined on the merits herein. Applicant’s preliminary amendment submitted July 28, 2023, is acknowledged wherein claims 1-7, 9-18, and 20 are amended, claims 19 and 21 are canceled, and new claims 22-24 are introduced.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 23 is 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 23, which depends from claim 10, specifies that “the alcohol is selected from isopropanol and ethanol.” However, claim 23 depends form claim 10, which further depends from claim 1. Both claim 1 and claim 10 make reference to an alcohol in different contexts. Therefore it is unclear whether the alcohol being described is the alcohol excluded from the precipitation solution in claim 1, or the alcohol added in the nucleic acid isolation step in claim 10. Since it is unclear which alcohol to apply this limitation to, the claim is indefinite.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 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 –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 18 and 20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Löper. (PCT international publication WO2016/009059, cited in PTO-1449)
Independent claim 18 claims a composition defined as a buffer containing a metal cation and a buffering agent, and not containing a polar protic or aprotic organic solvent, at pH 4 or less. In the present case, the pH value of 4 is written to only one significant figure, as opposed to being a more precise value such as 4.0. In the absence of any further definition, the most reasonable interpretation of this value is “rounds to 4 when expressed as one significant figure,” or more specifically “between 3.5 and 4.5”. While the buffer is described as being intended ”for precipitating proteins,” this statement of intended use does not structurally limit the composition of the precipitation buffer. Therefore claim 18 is infringed by any aqueous composition of a metal salt and a buffering agent in the absence of organic solvent at pH 4 or less regardless of whether the art describes it as a buffer for precipitating proteins. Dependent claim 20 requires that the buffer meet one of several conditions, one of which is that the metal ion is zinc.
Löper discloses a method of nucleic acid isolation including a metal cation induced protein precipitation step, wherein a polar protic or aprotic solvent is present in a concentration of 15% or less during the precipitation step. (p. 4 lines 21-33) Löper further describes the process as isolating both long (over 1000nt) and short (less than 200nt) RNA. A description of the process. (p. 4 line 35 – p. 5 line 13) describes the same steps recited in present claim 1, except for the presence of an organic solvent in the precipitant buffer. However, in the examples (pp. 41-55) experiments are performed controlling for various factors including the amount of organic solvent. (See examples 3-4 on pp. 43-44 and example 6 on pp. 48-49) In these experiments comparative controls were performed without an organic solvent present. (See XP (w/o DMSO) in table 2 and “water” in table on p. 48) As these controls were seen to isolate at least some RNA, they are reasonably considered to anticipate present claim 1. This buffer XP (p. 41 section 1) contains a dissolved salt of zinc as well as the buffer sodium acetate, and has a pH somewhere between 4-4.5, which as described above would reasonably, if rounded to one significant figure, be equal to the upper limit pH of 4 recited in claim 18. Therefore the solvent-free buffer which Löper prepared in the comparative examples testing precipitation in the absence of organic solvent would anticipate present claims 18 and 20.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 18 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Sigh et al. (PCT international publication WO2008/064686, Reference included with PTO-1449)
Independent claim 18 claims a composition defined as a buffer containing a metal cation and a buffering agent, and not containing a polar protic or aprotic organic solvent, at pH 4 or less. While the buffer is described as being intended ”for precipitating proteins,” this statement of intended use does not structurally limit the composition of the precipitation buffer. Therefore claim 18 is infringed by any aqueous composition of a metal salt and a buffering agent in the absence of organic solvent at pH 4 or less regardless of whether the art describes it as a buffer for precipitating proteins.
Sigh et al. discloses a method of purifying a protein from contaminating nucleic acids, comprising contacting a protein containing sample with a divalent transition metal cation. (p. 3 lines 4-26) In a preferred embodiment the divalent transition metal is Zn2+, as recited in one of the options of claim 20. (p. 20 lines 15-18) The precipitation of nucleic acid can be carried out at a pH having a range of 3-10) (p. 28 liens 12-14) Phosphate, which is a buffer according to the present claims, can be included in the mixture. (p. 28 lines 19-21)
It would have been obvious to one of ordinary skill in the art at the time of the invention to prepare a composition which is an aqueous solution of zinc and the buffer phosphoric acid, for use in the protein purification method described by Sigh et al. One of ordinary skill in the art would have seen the disclosure of Sigh et al. as suggesting that a solution having these components would be useful for the purpose of protein purification. While the intended use described by Sigh et al. is different than that recited in the claims, as discussed above the statement of intended use in the preamble of claim 18 does not serve to provide a structural limitation for the scope of the claim.
Still further, Sigh et al. does not specifically disclose the particular pH range of “4 or less” recited in claim 18. However, the broadest range (3-10) recited by Sigh substantially overlaps the claimed range. Therefore one of ordinary skill in the art would have recognized the pH as a result-effective variable and found it to be obvious to make such a buffer having a pH anywhere in the recited range, including the presently claimed portion of 3-4.
For these reasons the invention taken as a whole is prima facie obvious.
Claims 1-5, 7, 8, 12-15, 17, 18, 20, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Gundling. (US patent 5817798, cited in PTO-892)
Independent claim 1 claims a process for isolating nucleic acid from a sample comprising combining a precipitation buffer with the sample, wherein the precipitation buffer has pH 4 or less, does not contain an organic solvent, and contains a metal cation precipitant such that the final concentration of the metal cation is 200 mM or less. In the second step a protein precipitate is separated from a supernatant containing both long and short RNA, and in a third step a nucleic acid is isolated from the supernatant. Dependent claims 2-5 specify the pH and concentration of the precipitant solution.
Independent claim 18 claims a composition defined as a buffer containing a metal cation and a buffering agent, and not containing a polar protic or aprotic organic solvent, at pH 4 or less. In the present case, the pH value of 4 is written to only one significant figure, as opposed to being a more precise value such as 4.0. In the absence of any further definition, the most reasonable interpretation of this value is “between 3.5 and 4.5”. While the buffer is described as being intended ”for precipitating proteins,” this statement of intended use does not structurally limit the composition of the precipitation buffer. Therefore claim 18 is infringed by any aqueous composition of a metal salt and a buffering agent in the absence of organic solvent at pH 4 or less regardless of whether the art describes it as a buffer for precipitating proteins. Dependent claim 20 requires that the buffer meet one of several conditions, one of which is that the metal ion is zinc.
Gundling discloses methods for separating total RNA from other materials in a sample, and a further method for separating mRNA from total RNA, advantageously not using organic solvents. (p. 2 lines 10-16) This method involves exposing the sample to a transition metal precipitant and optionally a lytic agent. (column 2 lines 19-31) mRNA is then separated from the resulting sample by known methods such as oligo-TD matrices. (column 2 lines 32-38) In this context, “total RNA” is reasonably interpreted as including both long and short RNA as recited in present claim 1. The transition metal precipitant is selected from a list including for example zinc and copper, as recited in present claims 2 and 22. (column 3 lines 20-37) Typically, these are used at a concentration of 15-150 mM, which is less than 200 mM, as well as less than the upper limit of 175 mM in claim 3. The precipitant serves to precipitate various contaminants in the sample including proteins, while allowing for isolation of total RNA from the supernatant. (column 3 lines 4-19) Samples containing cells can also be treated with lytic agents including chaotropes and acidic pH of less than 5. (column 3 lines 37-58) After contacting the sample with the precipitant, the supernatant containing total RNA is separated from the precipitate (column 4 lines 7-20) and further processed to isolate mRNA from total RNA. (column 4 lines 21-24) In a specific embodiment (column 5 line 55 – column 6 line 15) a lysis buffer containing denaturing agents and 100 mM of the precipitant cobalt chloride is added to lyse and precipitate the sample.
While Gundling does not specifically describe adding a lysis/precipitation reagent having a precipitant metal such as a transition metal and a pH of less than 4.0, it would have been obvious to one of ordinary skill in the art at the time of the invention to carry out the process described by Gundling wherein the lysis/precipitation buffer has such a pH. Specifically, the disclosure by Gundling that an acidic pH of less than 5 can promote lysis of cells would suggest to one of ordinary skill in the art that pH is a result-effective variable in this step and motivate them to experiment with lower pH values, such as 4 or below.
Regarding claim 4, example 2 of Gundling described previously involves mixing a sample volume with another volume of lysis/precipitation buffer, a process that would necessarily dilute the starting concentration of the metal ion precipitant. Therefore in view of this fact, in order to obtain the desired final concentration of 15-150 mM of the metal ion, one of ordinary skill in the art would have been motivated to use a concentration of divalent metal higher than 150 mM, for example 250mM or higher, so as to achieve the target concentration in the final precipitation solution.
Regarding claims 7 and 8, the oligo-dT binding method described in example 2 of Gundling involves binding to a solid phase. It additionally is carried out in the supernatant from the precipitation step, which necessarily contains the chaotropic agent guanidinium isothiocyanate.
Regarding claim 5, the broadest range (2.5-4.0) recited in this claim would be obvious for the same reasons given previously with respect to the range “less than 4.0”.
Regarding claims 12-14, Gundling (e.g. example 2) describes lysis of the sample by adding a lysis buffer, for example before adding the precipitant.
Regarding claim 15, as discussed previously total RNA is isolated from the supernatant.
Regarding claim 17, example 2 of Gundling describes adding the precipitation buffer at a 1:1 ratio. (Equal volume)
Regarding claims 18 and 20, these claims are merely directed to the precipitant composition containing the transition metal. They would necessarily be infringed by making such a composition to carry out the method of claim 1.
For these reasons the invention taken as a whole is prima facie obvious.
Claims 9-11, 16, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Gundling as applied to claims 1-5, 7, 8, 12-15, 17, 18, 20, and 22 above, and further in view of Adams et al. (Reference included with PTO-892)
The disclosure of Gundling et al. is discussed above. Gundling et al. does not specifically disclose a method wherein the total RNA is then captured on a solid phase such as silica using a binding mixture comprising an alcohol. However, Gundling describes a variety of different solid phases can be used to collect the RNA from the supernatant. (column 4 lines 21-50)
Adams et al. discloses methods whereby silica magnetic beads are used to adsorb RNA from a solution. (p. 6062 right column) The specific protocol involved adding to a 25 µL sample 300 µL of aqueous binding buffer and 300 µL of ethanol, for a final concentration of about 48% ethanol, which falls within the range recited in present claims 9, 11, and 16, and then binding to magnetic silica particles. (p. 6063 left column second paragraph) The silica particles were seen to extract total RNA (both short and long) from the sample. (p. 6065 left column last paragraph)
It would have been obvious to one of ordinary skill in the art at the time of the invention to isolate the RNA from the supernatant produced by the method of Gundling et al. using the silica beads described by Adams. One of ordinary skill in the art would have understood that any existing prior art method for capturing RNA from solution could be used, depending on the fraction of RNA which they wished to collect.
For these reasons the invention taken as a whole is prima facie obvious.
Claims 9-11, 16, 23, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Gundling as applied to claims 1-5, 7, 8, 12-15, 17, 18, 20, and 22 above, and further in view of Madden et al. (PCT international publication WO2005/012487, Reference included with PTO-892)
The disclosure of Gundling et al. is discussed above. Gundling et al. does not specifically disclose a method wherein the total RNA is then captured on a solid phase such as silica using a binding mixture comprising an alcohol. However, Gundling describes a variety of different solid phases can be used to collect the RNA from the supernatant. (column 4 lines 21-50)
Madden et al. discloses methos of preparing short nucleic acids. (p. 6 paragraphs 19-20) In a preferred embodiment a sample comprising short RNA is added to a fluid mixture and bound to a solid phase in a column, then eluted. (p. 8 paragraphs 25-28) The fluid mixture can be produced as a mixture containing 50% of an alcohol. (p. 9 paragraph 29) Alternately, isopropanol can be substituted for ethanol. (p. 25 paragraph 110) In some examples the solid phase used is a silica based column. (e.g. p. 91 paragraph 292)
It would have been obvious to one of ordinary skill in the art at the time of the invention to short RNA from the supernatant produced by the method of Gundling et al. using the method described by Madden. One of ordinary skill in the art would have understood that any existing prior art method for capturing RNA from solution could be used, depending on the fraction of RNA which they wished to collect. In particular, Gundling already discloses a method for selectively isolating mRNA form the sample but does not provide guidance as to how other RNA fractions can be isolated if desired. Therefore one of ordinary skill in the art would look to improve the method of Gundling by additionally processing the supernatant with other purification techniques for isolating other fractions of the total RNA.
For these reasons the invention taken as a whole is prima facie obvious.
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 1-18, 20, and 22-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11725200. (Cited in PTO-892, herein referred to as ‘200) Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-19 of ‘200 anticipate the present claims. In particular, the claims of ‘200 are nearly identical to present claims 1-18, 20, and 22, with the exception that base claim 1 of ‘200 broadly excludes “aprotic polar solvents” from the precipitant mixture rather than defining “aprotic polar solvent” as referring only to C1-C5 alcohols. Regarding present claim 22, claim 2 of ‘200 describes zinc as an option for the metal cation. Regarding claims 23 and 24, claim 11 of ‘200 describes the alcohol as ethanol or isopropanol. Therefore the claims of ‘200 anticipate the present claims.
Conclusion
No claims are allowed in this action.
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/ANDREA OLSON/ Primary Examiner, Art Unit 1693 2/20/2026