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 .
This Office Action is in reply to Applicants' correspondence of 06/27/2025.
Applicants' remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicants' amendments. Any rejections or objections not reiterated herein have been withdrawn in light of the amendments to the claims or as discussed in this Office Action. This Action is made FINAL.
Please Note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Drawing Objections Maintained
The drawing objection set forth in the Office Action of 06/27/2025 are maintained. Applicant’s statement that there is no intention to have color drawings in the application is inconsistent with the instant specification. Paragraph [00043] of the instant specification states “The patent or patent application contains at least one drawing executed in color.” Furthermore, multiple figure descriptions in the instant specification rely on specific colors to understand the figures. For example: paragraph [00052] of Figure 9B describes data points as “gray points”, “red”, and “blue” to distinguish statistical categories in a volcano plot; paragraph [00053] of Figure 10B states, “Statistically significant clusters are labeled by color”; paragraph [00055] of figure 12 describes “[t]op panel dots are colored by disease activity assignment. Bottom panel dots are colored according to clinical flare event number. B. Unsupervised hierarchical clustering of genes differentially expressed between baseline and flare. Top bar indicates samples colored according to disease activity assignment. Bottom bar indicates samples colored according to clinical flare event number.”
Withdrawn Specification Objection
The specification objections set forth in the Office Action of 06/27/2025 are withdrawn in light of new specification submitted on 12/29/2025.
Withdrawn Claim Objections
The objections to claims 1, 6, 14, and 19 set forth in the Office Action of 06/27/2025 are withdrawn. Claims 6 and 16 have been cancelled. Claims 1, 14, and 19 have been amended to address the informalities identified in the Office Action.
New Claim Objections
Necessitated by Claim Amendments
Claims 1, 4, and 17 are objected to because of the following informalities:
Claim 1 recites “the volume of the one or more small volume sample” in step b but uses “the volume of the one or more small volume sample(s)” consistently throughout the remainder of the claim. The inconsistency in the use of this term within claim 1 is an informality.
Claim 1 additionally recites “comprising a ratio 28S to 18S RNA ratio,” which contains a redundant use of the term ‘ratio.’ The limitation should read either “comprising a 28S to 18S RNA ratio” or “comprising a ratio of 28S to 18S RNA”
Claim 4 retains the uncorrected typographical error “seves to purify” in step (c), which should read “serves to purify”.
Claim 17 retains the uncorrected typographical error “receptable” in step a, which should read “receptacle”.
Appropriate correction is required.
Withdrawn Claim Rejections - 35 USC § 112 - Indefiniteness
The rejections of claims 1-21 under 35 U.S.C. 112(b) as set forth in the Office Action of 06/27/2025 are withdrawn in light of the amendments to the claims and are replaced by the rejections set forth below.
Claim Interpretation - Maintained
Claims 17-21 recite a "kit" or a "system". The specification does not define these terms, so they are being interpreted to encompass any collection of reagents, components or consumables that include all elements of the claims.
Withdrawn Claim Rejections - 35 USC § 112(d)
The rejection of claim 16 under 35 U.S.C. 112(d) as set forth in the Office Action of 06/27/2025 are withdrawn. Claim 16 has been canceled.
Claim Rejections - 35 USC § 112 – Indefiniteness
New as Necessitated by Claim Amendments
Claims 2-3 and 9 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 1 recites “wherein the RNA quality and quantity is measured using an RNA integrity number (RIN) score comprising a ratio 28S to 18S RNA ratio” is indefinite. The instant specification acknowledges at paragraph [000158] that the 28S to 18S RNA ratio “can and was traditionally evaluated” as a measure of RNA integrity. Where the claim recites that “RNA quality and quantity is measured using an RNA integrity number (RIN) score”, a RIN score is a measure of RNA integrity, i.e., quality, and does not measure quantity. It is therefore additionally unclear how the RIN score serves as a measure of RNA quantity as recited in the claim.
Furthermore, the claim recites “the RNA has an RIN score of greater than 2,” but the instant specification at paragraph [000158] states that “RNA samples should score RIN of >7 on a scale of 1 (highly degraded) to 10 (highest integrity).” The claim’s threshold of greater than 2 is inconsistent with the specification’s own description of acceptable RNA quality, which sets the threshold at greater than 7.
Claim 2-15 depend from claim 1 and inherit these deficiencies.
Claim 2 is unclear in step (iv), which recites “binding the RNA to a silica based solid phase or column” It remains unclear whether the column is required to be silica based. The amendment renumbered the steps but left the language of step (iv) substantively unchanged from the original rejection. It is further unclear how the column functions in the claimed method because step (v) refers only to the “silica based solid phase” during elution step, leaving the role of the column unaddressed.
Claim 2 is unclear over recitation of the limitation “wherein the solution volume is 2-fold to 500-fold the volume of the one or more small volume sample(s)”, as recited in lines 18-19 of claim 2. Claim 2 recites limitations related to several solutions (i.e.: ethanol solution; salt solution; solution to produce a resuspended precipitate; organic extraction solution; solution to provide isolated RNA). In the unclear limitation it is unclear to which particular solution the limitation is intended to be applied to.
Claims 3 and 9 depend from claim 2 and inherit this deficiency.
Claim 4 is unclear over the phrase “wherein all buffer and solution volumes are reduced wherein a stabilization solution volume is 2-fold to 500-fold the volume of the one or more small volume sample.” It is unclear from what baseline the volume are reduced and to what extent.
Withdrawn Claim Rejections - 35 USC § 102
The rejections of claims 1, 5-7, and 13-16 under 35 U.S.C. 102(a)(1) as set forth in the Office Action of 06/27/2025 are withdrawn. Claims 5-8 and 16 have been cancelled. Claims 1, 13-15 have been amended to require a saliva sample, a limitation not disclosed by Speake et al, which is directed exclusively to fingerstick blood samples.
Claim Rejections - 35 USC § 103
New as Necessitated by Claim Amendments
Claims 1 and 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over Speake et al (2017) in view of Whitney et al (WO2012018639A2; published 02/09/2012) and Schroeder et al (The RIN: an RNA integrity number for assigning integrity values to RNA measurements. BMC Molecular Biol 7, 3 (2006). https://doi.org/10.1186/1471-2199-7-3).
Regarding instant claim 1, Speake teaches a method of obtaining 15 μL small volume samples self-collected by a patient at home by fingerstick, deposited into prefilled tubes containing 30 μL Tempus blood RNA stabilization solution that lyses cells and stabilizes RNA (p. 227, left column, para 3), representing a 2:1 solution-to-sample ratio and reading on the limitation “wherein the RNA stabilization solution volume is 2-fold to 500-fold the volume of the one or more small volume sample” of amended claim 1. Speake further teaches that the RNA generated from each sample was of sufficient quality for downstream transcriptomic analysis, including that the RNA quantity was sufficient for production of an RNA sequencing library suitable for full transcriptome profiling (p. 231, left column, para 1), and that RNA quality was assessed using a RIN score (Supporting information, Fig. S1b1). RNA of sufficient quality qPCR and sequencing library preparation, as demonstrated by Speake, necessarily has a RIN score greater than 2, as a RIN score of 1 indicates completely degraded RNA incapable of downstream molecular analysis.
With respect to the limitation, “wherein the RNA has an RIN score of greater than 2,” Schroeder teaches that the ratio of 28S to 18S ribosomal RNA was historically used as the standard measure of RNA quality, with RNA considered of high quality when the 28S:18S ratio is approximately 2.0 and higher (p. 2, right column, para 1).
Speake does not teach saliva as the sample type. Whitney teaches that human saliva is a suitable biological sample for RNA stabilization at ambient temperature without refrigerator (claim 17 and 25), and demonstrates stabilization of nucleic acids in 200 uL human saliva aliquots stored at room temperature without refrigeration (p. 171-172 – example 2; p. 174-176 – example 5). Whitney further teaches that disclosed compositions are capable of substantially preventing degradation on at least 70% of recoverable RNA from human saliva stored without refrigeration for at least 21 days (claim 25).
It would have been prima facie obvious before the effective filing date of the claimed invention for a person having ordinary skill in the art to have applied the small volume home collection and RNA stabilization framework of Speake to saliva samples in view of the teachings of Whitney. The skilled artisan would have been motivated by Whitney’s disclosure that human saliva is a suitable is matrix for RNA stabilization at ambient temperature, 200 uL saliva aliquots can be effectively stabilized in a lysis-capable solution during storage and transport without refrigeration, and that the compositions are capable of preventing RNA degradation in human saliva for extended periods (claim 25; p. 171-172 – example 2; p. 174-176 – example 5). The combination would have yielded predictable results because both references teach collection of small volume biological samples into RNA stabilization solutions for downstream nucleic acid analysis. With regard to the limitation of claim 1 that the RNA quality and quantity is measured using an RNA integrity number (RIN) score comprising a ratio 28S to 18S RNA ratio that is greater than 2, such a measurement of RNA would have been obvious in view of the teachings of Schroeder, which provides that such measurements were routinely made in the prior art, and that a score of 2 or higher is indicative of high quality RNA.
Regarding instant claim 13, Speake teaches a method applied to patients with type 1 diabetes, a disease (p. 227, left column, para 3).
Regarding instant claim 14, Speake teaches longitudinal RNA profiling of small volume samples collected from patients with disease at weekly intervals over six months (p. 227, left column, para 3). The substitution of saliva for blood as the sample type, as rendered obvious by the combination with Whitney, applies to the longitudinal monitoring aspect of claim 14.
Regarding instant claim 15, Speake teaches collection of small volume samples in series at regular weekly increments over six months (p. 227, left column, para 3). The substitution of saliva collection, as rendered obvious by Whitney, extends to the longitudinal collection series recited in claim 15.
Maintained Claim Rejections - 35 USC § 103
Modified as Necessitated by Claim Amendments
Claims 2, 4, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Speake et al (2017) in view of Whitney et al (WO2012018639A2) and Schroeder et al (2006) as applied to claim 1 above, and further in view of Hollaender (JP2012135317; published 07/19/2012).
Regarding instant claim 2, Speake and Whitney do not teach the specific RNA isolation. This deficiency is made up in the teachings of Hollander. Hollander teaches a method wherein RNA is isolated from small volume samples using a process comprising contacting the sample with a protease, followed by ethanol, where a precipitate is formed and DNase is added, the solution is passed through a silica membrane, and RNA is eluted with RNase-free water (p. 8, Example 1).
Regarding instant claim 4, Speake, Whitney, and Hollander teach a method wherein the sample is combined with a stabilization solution capable of lysing cells, followed by binding to RNA to a silica-based solid phase and elution of RNA with RNase-free water (Speake, p. 227, left column, para 3; Hollander, p. 8, Example 1).
Regarding instant claim 9, Hollander teaches that the protease used in the isolation is proteinase K (p. 8, Example 1). It would have been obvious to apply Hollander’s isolation protocol to the small volume saliva collection method rendered obvious by Speake and Whitney because Hollander explicitly teaches that its method is versatile and applicable to biological samples of all types including bodily fluids (p. 5, para 2-5; claim 29).
Claims 3 and 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Speake et al (2017) in view of Whitney et al (WO2012018639A2), Schroeder et al (2006) and Hollaender (JP2012135317; published 07/19/2012), and Wyrich (WO2014/146782, published 09/25/2014).
Regarding instant claim 3, Speake, Whitney, and Hollander do not teach removal of residual cellular material prior to RNA binding to solid phase, sequencing or RT-PCR of the isolated RNA, or the removal of non-target RNA species. This deficiency is made up in the teachings of Wyrich. Wyrich teaches a method of removing cellular material from the RNA isolation solution prior to binding RNA to solid phase (p. 41, last para).
Regarding instant claim 10, Wyrich teaches a method comprising sequencing the isolated RNA (p. 46, line 18), and Hollander teaches RT-PCR as a known downstream analysis method for isolated RNA from biological samples (p. 4, para 4).
Regarding instant claim 11, Wyrich teaches a method wherein RNA species not of interest are removed prior to sequencing (p. 44, line 4).
Regarding instant claim 12, Wyrich teaches a method wherein species specific RNAs are removed prior to sequencing (p. 44, line 4; p. 43, line 29). It would have been obvious to incorporate the cellular material removal and RNA species depletion steps of Wyrich into the method rendered obvious by Speake, Whitney, and Hollander because Wyrich teaches that its method is effective for stabilizing cell-containing biological material and allows for efficient isolation of nucleic acids with good yield (p. 4, para 2; p. 6, para 1-2).
Claims 17-21 are rejected under 35 U.S.C. 103 as being unpatentable over Speake (2017) in view of Thomas (US3883396A; published 05/13/1975) and further in view of Hollander (JP2012135317; published 07/19/2012).
Regarding instant claim 17, Speake teaches a home sample collection kit comprising capillary collection devices and prefilled tubes containing an RNA stabilization solution that lyses cells and stabilizes RNA, for self-collection of small volume samples and shipment to a laboratory for processing (p. 227, left column, para 3).
Speake does not teach a kit specifically directed to saliva samples. This deficiency is made up in the teaching of Thomas. Thomas teaches a diagnostic kit comprising a swab for sample collection, a tube with sample holding medium, personalized coded labels for anonymous patient identification, and a mail-transportable outer container for shipping samples to a testing laboratory (column 2, lines 24-37).
With respect to the limitation in step (a) that the collection means is for collection of a saliva sample, this limitation describes the intended use of the collection means rather than its structure. See MPEP 2111.02. A swab or receptable for a wash, spit, or aspirate as recited in step (a) is structurally identical to the collection means taught by Speake and Thomas regardless of the biological fluid intended for collection.
With respect to the structural limitation in step (b) that the tube contains an RNA stabilization solution comprising a mixture of chaotropic salt and phenol, Speake teaches a tube prefilled with an RNA stabilization solution that lyses cells (p. 227, left column, para 3). Hollaender acknowledges in the background of the prior art that phenol-containing solutions with chaotropic properties are well-established reagents for RNA stabilization, noting that “it is known from the prior art that RNA can be stabilized during storage using a reagent containing phenol, such as Trizol (p. 5, para 1). Trizol is a mixture of chaotropic salt (Guanidinium Isothiocyanate) and phenol.
It would have been prima facie obvious to a person having ordinary skill in the art to use a chaotropic salt and phenol solution as the RNA stabilization reagent in the collection kit of Speake, as such compositions were known in the art as effective RNA stabilization and cell lysis agents as acknowledged by Hollander.
It would have been prima facie obvious before the effective filing date of the claimed invention for a person having ordinary skill in the art to have combined the collection kit of Speake with labeled, mailable sample kit components of Thomas. The skilled artisan would have been motivated by the teachings of Thomas that a self-collection kit with coded labels and a mailing container maintains the sample during transport and allows patients or their representatives to receive results remotely (column 1, lines 32-36; column 2, lines 32-37), and would recognize that combination of known prior art elements to yield predictable results.
Regarding instant claim 18, Thomas teaches a kit comprising an envelope or mailing container shipment of samples to a laboratory (column 2, lines 24-37).
Regarding instant claim 19, Speake and Thomas teach a kit for self-collection of multiple small volume samples by a patient using collection means, tubes, labels, and mailing containers (Speake, p. 227, left column, para 3; Thomas, column 2, line 24-37).
With respect to claim 19, the courts have held that mere duplication of parts has no patentable significance unless a new and unexpected result is produced (In re Harza, 274 F.2d 669, 124 USPQ 378 (CCPA 1960). See MPEP 2144.04 VI.B.
Thus, the claimed sets and "numerous" labels and envelopes are devoid of patentable significance.
Regarding instant claim 20, Speake teaches a kit wherein the RNA stabilization solution volume is 30 uL, which is less than 1 uL and less than 500 uL (p. 227, left column, para 3).
Regarding instant claim 21, Speake teaches a kit wherein the collection capillary holds 15 uL and the tube containing the RNA stabilization solution has a total volume capacity of 1.5 uL (p. 227, left column, para 3).
Response to Remarks
Applicant has traversed the rejections set forth in the Office Action of 06/27/2025 under 35 U.S.C. 102(a)(1) and 35 U.S.C. 103. Applicant’s arguments have been fully and carefully considered but are not found persuasive for the reasons set forth below.
With respect to the 35 U.S.C. 102(a)(1) rejections for claims 1 and 13-15, Applicant has amended claim 1 to require that the sample comprises saliva. Because Speake is directed exclusively to fingerstick blood samples and does not disclose saliva as a sample type, the 102 rejections for these claims are withdrawn as detailed above and replaced with new 103 rejections in view of Whitney.
With respect to the 35 U.S.C. 103 rejections, Applicant has argued that because Speake does not disclose saliva samples, there is no motivation to substitute saliva for blood and no reasonable expectation of success in performing RNA profiling and analysis with small volume saliva samples. These arguments are not persuasive.
Applicant contends that there is no motivation for a skilled artisan to replace blood samples with saliva. This argument does not account for the teachings of Whitney, which explicitly discloses human saliva as a suitable biological sample for RNA stabilization at ambient temperature without refrigeration (claim 17; claim 25; p. 171-172 – example 2; p. 174-176 – example 5). Whitney provides a direct teaching that saliva RNA is stabilizable, which is the motivation Applicant argues is lacking.
Applicant further argues that a skilled artisan would have no reasonable expectation of success because saliva presents unique technical challenges, including high endogenous RNase concentrations and a viscous, mucoid matrix that complicates RNA extraction. Whitney directly demonstrates that nucleic acids, including RNA as recited in claim 25, can be stabilized in huma saliva at ambient temperature without refrigeration for extended periods (claim 25; p. 171-172 – example 2; p. 174-176 – example 5). The applicant’s characterization of saliva as presenting an insurmountable barrier to RNA stabilization is contradicted by the express teachings of Whitney and accordingly does not establish a lack of reasonable expectation of success.
With respect to the maintained and modified 103 rejections for claims 2-4, 9-12 and 17-21. Applicant’s arguments addressed the prior rejection of the original claims over Speake, Hollander, Wyrich, and Thomas. As those claims have been amended, the rejections have been modified to incorporate Whitney into the combination. The arguments presented by Applicant do not address the modified rejections as set forth herein, which now rely on the combination of Speake, Whitney, and the remaining references to address the saliva limitation introduced by amendment.
Conclusion
All claims stand rejected.
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.
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/NURA M. CHOUDHURY/ Examiner, Art Unit 1683
/STEPHEN T KAPUSHOC/ Primary Examiner, Art Unit 1683
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