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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-5, 7-11, 15-17, 21, 22, 24-27, and 69) in the reply filed on 12/30/25 is acknowledged.
The Restriction Requirement is still deemed proper and is therefore made FINAL.
Claims 28-30, 33-36, 38-42, 45, 49-51, 53, 55-59, and 61 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/30/25.
Claim Status
Claims 6, 12-14, 18-20, 23, 31-32, 37, 43-44, 46-48, 52, 54, 60, and 62-68 have been canceled without prejudice or disclaimer. Currently, claims 1-5, 7-11, 15-17, 21, 22, 24-27, and 69 are under consideration.
Priority
5. This application has a priority date of July 9, 2020: This application is a national stage application under 35 U.S.C. § 371 of International Application No. PCT/FI2021/050529, filed July 7, 2021, which claims priority benefit to Finland Application No. 20205738, filed July 9, 2020.
Information Disclosure Statement
6. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other
Information submitted for consideration by the Office, and MPEP § 609 A(1) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the examiner on form PTO-892 or applicant on form PTO-1449 lists the references, they have not been considered.
7. The information disclosure statements filed 1/9/23, 5/23/23, 4/28/25, 8/15/25, and 5/28/26 have been considered as to the merits prior to First Action on the Merits.
Specification
8. The use of the terms “TWEEN” and “TRITON”, which is a trade name or a mark used in commerce, has been noted in this application. For example, see page 21-lines 31 and 33; pages 45, 46, 48, and 49. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Please check the entire specification for trademark corrections.
Abstract
9. This application does not contain an abstract of the disclosure as required by 37 CFR 1.72(b). An abstract on a separate sheet is required.
Claim Objections
10. Claims 1, 2, 3, 4, 7, 8, 10, 15, 16, 16, and 22 are objected to because of the following informalities: The claims utilize several acronyms “NAD+, NADP+, NADH, NADPH, °C, NAD, GSH, GSSG, etc.” without first defining what it represents in the independent claim. While the claims can reference acronyms, the material presented by the acronym must be clearly set forth at the first use of the acronym. However, Applicant is cautioned not to introduce new matter into the claims. Appropriate correction is required.
11. Claims 1-5, 7-11, 15-17, 21, 22, 24-27, and 69 appears to have several typos involving the article “a” verses “the”. The appropriate article in the first recitation is “a” and all subsequent wording should be directed to “the”. For example, “a sample” is recited in claim 1 lines 3 and 5. After the first “a sample” all other references should be to “the sample”. Appropriate correction is required.
12. Claim 1 step A reads “contacting a sample with pre-heated to at least 40°C” after the amendment filed on 7/6/23. Please correct the typo.
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.
13. Claims 1-5, 7-11, 15-17, 21, 22, 24-27, and 69 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.
A. Claim 1 is vague and indefinite because it is unclear as to what the “method steps” will encompass. The claim is directed to steps A; B or C; and D. Accordingly the method can comprise steps A, B, and D or steps A, C, and D. However, the body of the claim appears to require measurement including B and C. This is unclear as step B analyzes first and second parts while step C analyzes third and fourth parts. Are steps B and C independent of each other or will the method require both processes for practice? The intended scope of the method is ambiguous and the metes and bounds of the claim cannot be determined. Appropriate correction is required.
B. Claims 1, 22, and 24 recites the limitation "the high temperature" in claim 1. There is insufficient antecedent basis for this limitation in the claim. Claim 1 never recites “a high temperature”. Applicant should recite ‘a high temperature” in the first instance for clarity. Appropriate correction is required.
C. Claims 2, 3, 7, 15, 17, and 21 are vague and indefinite in reciting multiple and, or, and/or clauses in a single claim. The wording does not clearly set forth the intended scope or limitations. It is suggested that the claims are written in proper Markush form in order to obviate the rejection.
D. Claims 5 and 9 contains the trademark/trade name [TWEEN, TRITON, ELLMAN’S REAGENT]. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe reagent detergents/reporters and, accordingly, the identification/description is indefinite.
E. Regarding claim 11, the phrase "optionally" and parenthesis renders the claim indefinite because it is unclear whether the limitations following the phrase or within the symbol () are part of the claimed invention. See MPEP § 2173.05(d). See reaction(s) and is(are). It is suggested that the phrase and () are omitted in order to obviate the claim.
F. Claim 24 recites the limitation "contact time" in claim 1. There is insufficient antecedent basis for this limitation in the claim. Claim 1 merely recites contacting. Applicant should employ consistent language for clarity. Appropriate correction is required.
G. The term “about” in claims 22, 24, and 25 is a relative term which renders the claim indefinite. The term is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
For example, as recited it is not clear if about 40-70% concentration is intended to read on concentrations of 2%, 5%, 10%, 100%, 110%. It is suggested that the term “about” is omitted in order to obviate the rejection.
Claim Rejections - 35 USC § 103
14. 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.
15. Claim(s) 1, 2, 7, 11,15-17, 21, 22, 24-26, and 69 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gowda et al. (Anal. Chem. 2017 April 18; 89(8):4620-4627) in view of Gonzalez et al. (Yeast, Vol.14, pages 1347-1355, 1997) and Sellick et al. (Metabolomics, 18 May 2010; Vol.6, pages 427-438).
Gowda et al. disclose a simple 1H NMR experiment that can simultaneously measure coenzymes and antioxidants in extracts of whole human blood, in addition to the nearly 70 metabolites that were previously shown to be quantitated in serum/plasma.
Coenzymes of redox reactions: oxidized/reduced nicotinamide adenine dinucleotide (NAD+ and NADH) and nicotinamide adenine dinucleotide phosphate (NADP+ and NADPH); coenzymes of energy including adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP); and antioxidants, the sum of oxidized and reduced glutathione (GSSG and GSH) can be measured with essentially no additional effort. A new method was developed for detecting many of these unstable species without affecting other blood/blood plasma metabolites. The identities of coenzymes and antioxidants in blood NMR spectra were established combining 1D/2D NMR techniques, chemical shift databases, pH measurements and, finally, spiking with authentic compounds. See abstract.
Gowda et al. demonstrate that their quantitative serum/plasma-based approach can be extended to whole blood metabolomics to expand the metabolite pool and encompass physiologically sensitive coenzymes of redox reactions and energy, as well as antioxidants, in addition to the nearly 70 blood metabolites that were quantified in serum/plasma. See page 3.
Each protein precipitation/metabolite extraction method used 200 to 400 μL of whole blood, plasma, or RBCs. The biospecimens were mixed with cold methanol in a 1:2 sample/methanol (v/v) ratio, 55% methanol in a 1:9 ratio, methanol/chloroform in a 1:2:2 or 1:3.3:6.6 ratio or 4% trichloroacetic acid in a 1:5 ratio (Table S1). All sample solutions were then vortexed for 30 s, sonicated for 2 min at 4 °C, and incubated at −20 °C for 20 min. The mixtures were centrifuged at 13 400 rcf for 30 min to pellet proteins and cell debris. Clear aqueous solutions were transferred to fresh vials and dried using an Eppendorf Vacufuge-Plus vacuum concentrator for 5 h.
Dried samples were mixed with 600 μL phosphate buffer containing 25 μM TSP, spun to sediment any residue, and the supernatants were transferred to 5 mm NMR tubes for analysis. See page 4.
Gowda et al. differ from the instant invention in not specifically teaching an incubation at high temperatures of 40-80°C for 10sec-10min.
However, Gonzalez et al. teach a simple and reliable method for the efficient inactivation of metabolism and for quantitative metabolite extraction from yeast cells.
The method is based on the use of a boiling solution made of 75% ethanol (volume/final volume) buffered with 70 mM-Hepes (final concentration), pH 7.5, to guarantee the stability throughout the whole procedure of a large variety of metabolites, including all
glycolytic intermediates, nucleotides, pyridine nucleotides and organic acids compounds. The extraction is fast, requiring only 3 min incubation of yeast cells in the ethanol-buffered mixture maintained at 80 degrees C. It can be carried out either directly by spraying the cells into the boiling mixture, or after quenching the whole culture in 60% methanol kept at -40 degrees C.
Extracts are subsequently concentrated by evaporation under partial vacuum and the residue is resuspended in a small volume of water. This concentration step and the use of a highly sensitive analytical method allow us to quantify metabolites in less than 10 mg dry weight cells. This method, which can be applied to other fungi, could be very helpful for the determination of true metabolites in mutants and for metabolic flux analysis. See abstract.
While, Sellick et al. disclose methods of optimizing extraction procedures for metabolite targets. The extraction methods tested included cold methanol, hot ethanol, acid, alkali and methanol/chloroform plus combinations thereof. The extraction of metabolites using two 100% methanol extractions followed by a final water extraction recovered the largest range of metabolites. For the majority of metabolites, extracts generated in this manner exhibited the greatest recovery with high reproducibility. Therefore, this was the best extraction method for attaining a global metabolic profile from a single sample. However, another parallel extraction method (e.g. alkali) may also be required to maximize the range of metabolites recovered (e.g. non-polar metabolites). See abstract.
In the hot ethanol procedure, a cell pellet was resuspended in 1 ml 90°C 100% ethanol and incubated at 90°C for 10 min. The samples were cooled on ice for 5 min, centrifuged at 15,000×g for 1 min and the supernatant removed and lyophilized. See section 2.4.3 The extraction with hot ethanol provided excellent recovery of fatty acids (e.g. stearic acid and palmitic acid). It is likely that this was due to the combination of heat and organic solvent increasing the solubility of the fatty acids.
As with cholesterol detection, decreasing the methanol:water ratio significantly decreased the recovery of fatty acids (see Fig. 7a). These data highlight the importance of using appropriate extraction processes for targeted analysis of specific metabolic pathway components.
Gonzalez et al. teach extraction procedure in yeast cell, while Sellick et al. teach extraction in mammalian cells (CHO cells).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the hot ethanol or boiling solution extract procedure taught by Gonzalez et al. and Sellick et al. into the method of Gowda et al. as a means for generating stable metabolites, allowing for complete permeabilization (including fatty acids) for total and reproductible release of the metabolites, with accurate and valid results. See Gonzalez et al. -page 1350, 1st column, Results and Discussion. And Sellick et al. -page 435.
One skilled in the art would have been motivated to employ the boiling extraction of Gonzalez et al. and Sellick et al. to guarantee the stability throughout the whole procedure of a large variety of metabolites, including all glycolytic intermediates, nucleotides, pyridine nucleotides and organic acids compounds with quick extraction, requiring only 3 min incubation in an ethanol-buffered mixture maintained at 80 degrees C. See abstract of Gonzalez et al. and abstract, section 2.4.3, and page 435 of Sellick et al.
It is noted that KSR forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See recent Board decision Ex parte Smith,— USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007)(citing KSR, 82 USPQ2d at 1396).
Double Patenting
16. 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.
17. Claims 1, 7, 15-17, 21, 22, 24, 26, and 69 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 25, 27-29, and 31-35 of copending Application No. 19/037,543 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims are drawn to methods of preparing an extract comprising metabolites from a sample of a subject, wherein the method comprises: allowing the sample to contact with a non-buffered alcohol solution, with an alcohol concentration of about 30-80% at a high temperature of about 40 — 80 °C to obtain a mixture of the sample and the alcohol solution; whereby metabolites are analyzed.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 1, see claims 25 and 27 of the ‘543 application.
Regarding claim 7, see claims 32 and 35 of the ‘543 application.
Regarding claim 15, see claims 32 and 35 of the ‘543 application.
Regarding claim 16, see claim 31 of the ‘543 application.
Regarding claim 17, see claim 31 of the ‘543 application.
Regarding claim 21, see claim 25 of the ‘543 application.
Regarding claim 22, see claims 25, 33, and 34 of the ‘543 application.
Regarding claim 24, see claim 28 of the ‘543 application.
Regarding claim 26, see claim 29 of the ‘543 application.
Regarding claim 69, see claim 25 of the ‘543 application.
18. For reasons aforementioned, no claims are allowed.
Remarks
19. Prior art made of record and not relied upon is considered pertinent to the applicant’s disclosure:
A. Kamlage et al. (WO2015/145387A1) disclose blood sampling for metabolite measurements.
B. Lazzarino et al. (Analytical Biochemistry, 322 (2003) pages 51-59) disclose a simple and reliable method for the preparation of biological samples for the evaluation of biochemical parameters representative of the redox and energy states, such as glutathione (GSH), oxidized glutathione (GSSG), oxidized nicotinamide adenine dinucleotide (NAD+), reduced nicotinamide adenine dinucleotide (NADH), oxidized nicotinamide adenine dinucleotide phosphate (NADP+), reduced nicotinamide adenine dinucleotide phosphate (NADPH), coenzyme A (CoASH), oxidized CoASH, ascorbate, malondialdehyde, oxypurines, nucleosides, and energy metabolites.
20. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LISA V COOK whose telephone number is (571)272-0816. The examiner works a flexible Part-Time schedule but can normally be reached on Monday, Thursday, and Friday from 9am to 5pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached on 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Lisa V. Cook
Patent Examiner
Art Unit 1642
Hoteling
6/13/26
/LISA V COOK/Primary Examiner, Art Unit 1642
Prosecution Insights