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 .
Status of the Claims
Claims 1-3, 5, and 15 are pending. Claims 1-3, 5, and 15 are the subject of this FINAL Office Action.
Claim Interpretation
The claims are interpreted under the broadest reasonable interpretation. Claim 1 is a very broad claim. Claim 1 requires synthesizing cDNA from sample RNA through reverse transcription and amplifying the cDNA by multiplex PCR, but does not provide further limitations of how the reverse transcription and multiplex PCR is to be performed, so long as they are performed in the presence of T4GP32 or a variant thereof.
The claim will be interpreted as encompassing any method of synthesizing cDNA from sample RNA derived from skin surface lipid through reverse transcription and any method of amplifying the cDNA by multiplex PCR, so long as they are performed in the presence of T4GP32 or a variant thereof.
Multiplex PCR will be interpreted in accordance with par. 0002 of the specification as any method of amplifying more than one region of a nucleic acid sample using a plurality of primer pairs at the same time.
Maintained - 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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-3, 5, and 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Woo et al. (US 2015/0184228 A1, cited on the IDS filed 02/14/2024) in view of Inoue et al. (US 2018/0371524 A1, cited on the IDS filed 07/08/2022) and evidenced by Morrical et al. (WO 2004/063352 A2; previously cited).
Regarding claim 1, Woo teaches that the reverse transcription of RNA followed by PCR cDNA amplification (RT-PCR) has become widely used for the detection and quantification of nucleic acid targets (par. 0003-006), and teaches that the RT-PCR can be performed in a one-step procedure (par. 0011).
Woo teaches that the PCR can be multiplex PCR (par. 0030)
Woo teaches that one or more PCR inhibitor blocking agents can be added to assist in overcoming the inhibition of PCR reaction, including DNA binding proteins such as T4GP32 (par. 0081).
Woo does not teach that the sample RNA is derived from skin surface lipid, but does teach that the nucleic acid samples can be derived from skin (par. 0109).
Inoue teaches a method of isolation nucleic acid from skin surface lipids collected from a subject (Abstract). Inoue teaches that skin is a tissue from which biological samples can be collected minimally invasively (par. 0004), and teaches that lipids present on the skin surface of a subject comprise a nucleic acid derived from a skin cell of the subject, and that a gene analysis and condition diagnosis of a subject can be performed in a convenient and minimally invasive manner and more comprehensively by analyzing a nucleic acid in lipids present on the skin surface of a subject (par. 0017).
It would have been obvious to one of ordinary skill in the art to substitute the skin sample of Woo with RNA derived from skin surface lipid, as Inoue teaches analysis of skin surface lipids can be performed in a convenient and minimally invasive manner and more comprehensively by analyzing a nucleic acid in the skin surface lipids, and would be a simple substitution of RNA from one sample source for another, with no evidence of unexpected results.
Regarding claim 2, Woo teaches the use of T4GP32. As evidenced by Morrical, SEQ ID NO: 1 is the sequence for T4GP32 (pg. 6, lines 32-33; search results reproduced below).
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Regarding claims 3 and 15, Woo teaches the primers can be random primers (par. 0093).
Regarding claim 5, Woo teaches the PCR inhibitor blocking compounds can be added to give a final concentration in a working solution of about 1 ng/µL to 10,000 ng/µL (par. 0086) (ng/µL is equivalent to µg/mL), which encompasses the range provided in the claim. It would have been obvious to one of ordinary skill in the art to use 1 to 100 µg/mL, as this is within the range taught by Woo.
Maintained - 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 1-3, 5, and 15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 8, and 12 of copending Application No. 18/276,844 (reference application) in view of Woo (US 2015/0184228 A1). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference application anticipates claims 1-2 of the instant application, and makes obvious claims 3, 5, and 15 in view of Woo.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conflicting claim 1 of the reference application is a species of the broader instant claim 1. Conflicting claim 1 recites:
A method for preparing a nucleic acid sample derived from skin stratum corneum, the method comprising:
extracting RNA from stratum corneum collected from a skin surface to prepare an ethanol aqueous solution containing the RNA, wherein the stratum corneum is stratum corneum within a depth of 5 pm from the skin surface;
contacting the RNA in the water-soluble alcohol aqueous solution with a silica-based solid-phase material to separate the RNA, wherein a concentration of the ethanol in the ethanol aqueous solution is from 40 to 46 vol% before the contact with the silica-based solid-phase material;
and reverse-transcribing and amplifying, the separated RNA in the presence of single-stranded nucleic acid-binding protein to prepare a nucleic acid sample, wherein the amplification is amplification by multiplex PCR, and the single-stranded nucleic acid-binding protein is T4GP32 or a variant thereof.
Instant claim 1 recites:
A method for amplifying a nucleic acid, the method comprising:
synthesizing cDNA from sample RNA derived from skin surface lipid through reverse transcription; and
amplifying the cDNA by multiplex PCR, wherein
the reverse transcription and the multiplex PCR are performed in the presence of a single-stranded nucleic acid-binding protein, and the single-stranded nucleic acid-binding protein is T4GP32 or a variant thereof.
As conflicting claim 1 requires the limitations of instant claim 1, conflicting claim 1 anticipates the instant claim 1.
Conflicting claim 12 anticipates instant claim 2 as they both require the sequence of T4GP32.
Conflicting claim 8 recites that the initial concentration of the single-stranded nucleic acid-binding protein is from 3 to 300 µg/mL. Instant claim 5 requires the concentration of be from 1 to 100 µg/mL. It would have been obvious to one of ordinary skill in the art to choose a concentration of 100 µg/mL or less, as the conflicting claim encompasses the range of the instant claims.
Conflicting claim 1 recites the use of multiplex PCR, but does not require the use of random primers. Woo teaches that multiplex PCR can be performed with random primers (par. 0093). It would therefore be a simple substitution for the multiplex PCR required by the conflicting claims for the multiplex PCR performed with random primers as taught by Woo, with no evidence of unexpected results.
Response to Arguments
Applicant's arguments filed 01/12/2026 have been fully considered but they are not persuasive.
Applicant argues that a person of ordinary skill in the art would not have had a reasonable expectation of success in achieving the claimed method, and argues that any case of obviousness is more than rebutted by the surprising results that are tied directly to the use of T4GP32 in the presently claimed methods.
Applicant states that Woo does not provide a method for amplifying a nucleic acid that uses T4GP32, but merely lists bovine serum albumin (BSA), fish gelatin, T4GP32, and other additives as possible options for PCR, without identifying T4GP32 as preferred, distinguishing it from the others, or suggesting it would enhance reverse transcription or multiplex PCR efficiency. Applicant further states that selection of T4GP32 without directional teaching in Woo necessarily depends upon impermissible hindsight reconstruction.
This is not found persuasive. Woo teaches that T4GP32 was a known PCR inhibitor blocking agent (par. 0081), and thus would be obvious to one of ordinary skill in the art to use in a PCR reaction as it was a known option. Additionally, Woo states that BSA, fish gelatin, and T4GP32 are preferred proteins for use as PCR inhibitor blocking agents (par. 0081). Woo’s use of BSA and fish gelatin in the methods of Woo do not constitute a teaching away from the use of T4GP32, particularly as T4GP32 is stated to be a preferred protein.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In response to Applicant’s arguments that the present application provides unexpected results of markedly improved sensitivity and yield in multiplex RT-PCR when T4GP32 is present in both the reverse transcription and multiplex PCR steps, this is not found persuasive. Unexpected results must be commensurate in scope with the claimed invention (MPEP 716.02(d)). Claim 1 encompasses any method of synthesizing cDNA from sample RNA derived from skin surface lipid through reverse transcription and any method of amplifying the cDNA by multiplex PCR, so long as they are performed in the presence of T4GP32 or a variant thereof.
Applicant’s specification uses one particular assay for the reverse transcription and multiplex PCR steps with one concentration of T4GP32 to show improved results. However, the claims encompasses all methods of reverse transcription, all methods of multiplex PCR, and all concentrations of T4GP32. The results cited by Applicant are therefore not commensurate in scope with the claims, as the results are applicable to one particular assay while the claims encompass all methods of reverse transcription and multiplex PCR.
Furthermore, Chandler et al. (Reverse transcriptase (RT) inhibition of PCR at low concentrations of template and its implications for quantitative RT-PCR. Applied and Environmental Microbiology. February 1998, 64(2):669-677; cited on the IDS filed 07/08/2022) shows the addition of T4GP32 during the reverse transcription phase of RT-PCR increases the RT-PCR product yield by as much as 483% (Abstract), showing that a 2.19 increase in relative yield is not unexpected.
Conclusion
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 Randi L Beil whose telephone number is (571)272-1147. The examiner can normally be reached M-F 8:00 am - 5:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Heather Calamita can be reached at 571-272-2876. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/R.L.B./Examiner, Art Unit 1684 /HEATHER CALAMITA/Supervisory Patent Examiner, Art Unit 1684