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 office action is a response to applicant’s communication submitted August 21, 2026, wherein claims 1, 5, 6, 14, 16, 18, 20, and 23 are amended. 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.
Claims 1-18, 20, and 22-24 as amended are examined on the merits herein.
Withdrawn Rejections
Applicant’s amendment, submitted August 21, 2026, with respect to the rejection of claim 23 under 35 USC 112(b) for being unclear as to what alcohol is being referred to, has been fully considered and found to be persuasive to remove the rejection as claim 23 has been amended so as to clearly refer to the alcohol used to prepare the binding condition. Therefore the rejection is withdrawn.
Applicant’s amendment, submitted August 21, 2026, with respect to the rejection of claims 18 and 20 under 35 USC 102(a)(1) for being anticipated by Loper et al., has been fully considered and found to be persuasive to remove the rejection as claim 18 has been amended to define the pH of 4.0 to one significant digit, excluding the slightly higher pH recited in Loper’s examples. Therefore the rejection is withdrawn.
Applicant’s amendment and arguments, submitted August 21, 2026, with respect to the rejection of claims 18 and 20 under 35 USC 103 for being obvious over Sigh et al., have been fully considered and found to be persuasive to remove the rejection as the pH range described by Sigh only narrowly overlaps the claimed range and Applicant has demonstrated that a pH of below 4.0 results in unexpectedly increase values for RNA isolation. Therefore the rejection is withdrawn.
The following rejections of record in the previous action are maintained:
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 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, of record in previous action)
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 4.0 or less, does not contain an organic solvent, contains a buffer which is a combination of a carboxylic acid and its corresponding carboxylate salt, 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 4.0 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. 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 of record in previous action)
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 of record in previous action)
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. (of record in previous action, 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.
Response to Arguments
Applicant’s arguments, submitted August 21, 2026, with respect to the above grounds of rejection, have been fully considered and not found to be persuasive to remove the rejections.
Regarding the rejection over Gundling et al. US5817798, Applicant makes several arguments. Firstly, Applicant argues that the amendment to claim 1 requiring that the precipitation buffer contains both a carboxylic acid and its carboxylic acid salt differentiates the claims from the prior art. However, as disclosed in example 2 (column 5 lines 64-65) the precipitation buffer can contain lithium acetate. However, since acetate is the conjugate acid of acetic acid, at acidic pH it would reasonably be expected that it would exist as both the neutral acid (acetic acid) and the conjugate base (lithium acetate) in equilibrium. Therefore an acidic solution of lithium acetate would be expected to meet this limitation.
Secondly, Applicant argues that Gundling describes the acidic pH as a lysis agent rather than a precipitation agent, and does not describe the acetate as part of a precipitation buffer for maintaining the pH at a particular value. However, as discussed in MPEP 2144(IV) “The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant.” Therefore the fact that the prior art does not specifically describe these components as being for the purpose of precipitating proteins does not differentiate the claimed process from the prior art. As described in column 3 lines 4-19 and example 2 in columns 5-6, a single solution containing both a lytic agent and a transition metal serves to both lyse cells and precipitate non-RNA cellular debris including proteins. Therefore the intended function of the individual components described in the present claims does not serve to differentiate the claims from the prior art.
Still further, Applicant argues that Gundling allows for a very wide of either neutral, basic, or acidic pH, rather than specifically directing one of ordinary skill in the art to an acidic pH. However, the various pH ranges described in the prior art are not given as a single broad range, but rather as three different ranges that can be used as alternatives to one another. In particular the neutral pH of 6-8 is specifically described as being used if one of ordinary skill in the art is using a particular denaturant such as a chaotrope or detergent. (column 3 lines 45-52) As an alternative to such agents the reference suggests either acidic or alkaline pH. Therefore “chaotrope/detergent,” “alkaline,” and “acid” are described as three discrete lysis conditions, and one of ordinary skill in the art would have specifically selected from among them, which is a different situation from the prior art simply disclosing one extremely broad pH range. Having settled on an acidic pH as one of these three possible solutions, deciding to then use a pH of 4.0 or less would be obvious.
Finally, Applicant argues that the process described by Gundling would not necessarily result in the isolation of small RNA, based on the description by Gundling of isolating mRNA, which is a large RNA having a typical size of at least 1000 nucleotides and being distinct from smaller RNA having a size of 200 nt or less. However, while Gundling specifically describes isolation of mRNA as a goal, the reference specifically notes (column 2 liens 43-57) that the separation method isolates total RNA, which is described as including “genomic RNA, subgenomic RNA fragments, mRNA, tRNA, and rRNA.” This is not a mixture containing only mRNA. Obtaining purified mRNA requires a further step, such as contacting the soluble total RNA with an oligo-dT matrix. (column 3 liens 14-19) Since tRNA has a length of less than 200 nucleotides and is ubiquitous in all cells engaged in translating proteins, it is reasonably expected that any use of Gundling’s method to lyse cells would result in an initial mixture of total RNA containing at the very least mRNA having a size of over 1000 nt and tRNA having a size of less than 200 nt.
Regarding the rejection of claims 9-11, 16, and 23 over Gundling further in view of Adams, Applicant relies on the same rationale discussed above, and further argues that Adams teaches away from the claimed invention because the denaturing solution described by Adams comprises 2-mercaptoethanol, which is a protic organic solvent. However, Adams is cited solely for the purpose of defining the isolation step c), which does not include the above exclusionary proviso. Gundling specifically suggests using a solid support such as an oligo-dT matrix to purify the extracted RNA after the lysis/precipitation step, (e.g. column 4 lines 21-50) and the disclosure of Adams is relied upon to provide an example of such an oligo-dT matrix, not to suggest modifications to the lysis/precipitation step which is already describe by Gundling. Therefore the fact that Adams does not describe all the elements of steps a) and b) in claim 1 is not relevant to the finding of obviousness.
The arguments with respect to the reference Madden et al. are found not persuasive for similar reasons, as the elements not disclosed by Madden are already disclosed by Gundling.
For all of these reasons the rejections over Gundling, Gundling in view of Adams, and Gundling in view of Madden are deemed proper and maintained. Applicant has declined to traverse the rejection of claims 1-18, 20, and 22-24 for claiming the same invention as US patent 11725200. Therefore this rejection is maintained as well.
Conclusion
No claims are allowed in this action. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDREA OLSON whose telephone number is (571)272-9051. The examiner can normally be reached M-F 6am-3:00pm.
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/ANDREA OLSON/ Primary Examiner, Art Unit 1693 10/1/2026
