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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-13) in the reply filed on February 27, 2026 is acknowledged.
Claims 14-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 February 27, 2026.
Claims 1-13 are under examination.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The Information Disclosure Statement filed August 31, 2023 has been considered.
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 § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The use of the terms FUJIFILM WAKO® at paragraphs [0067, [0106], and [0133]; and HORIBA® at paragraphs [0067] and [0156]; which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear 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.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. The courts have stated:
To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious" and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966; Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co., the court stated:
A written description of an invention involving a chemical genus, like a description of a chemical species, "requires a precise definition, such as by structure, formula, [or] chemical name," of the claimed subject matter sufficient to distinguish it from other materials. Fiers v. Revel, 984 F.2d at 1171,25 USPQA2d, 1601; In re Smyth, 480 F.2d 1376,1383, 178 USPQ 279,284 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is an unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is "not a sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence." MPEP § 2163. The MPEP does state that, for a generic claim, the genus can be adequately described in the disclosure presents a sufficient number of representative species that encompass the genus. MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitutes a sufficient number of representative species, the courts have indicated what does not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d at 1012, 10 USPQ2d at 1618. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial Structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed structure, and v. Correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art.
A "representative number of species" means that the species, which are adequately described, are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. This disclosure of only one or a few species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 115; Noelle v. Lederman, 355 F.3d, 1343, 1350, 69 USPO2d 1508, 1514 (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). In addition, it has been well known that minor structural differences even among structurally related compounds can result in substantially different biology, expression, and activities. The instant claims require that the detection of a microRNA in a biological sample. The rejected claims thus comprise a method of detecting a genus microRNAs, but does not provide a method for detecting all miRNAs or how do use all miRNAs for use as disease markers in all types of cancer or dementia. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification states that “microRNAs are contained in extremely small amounts in biological samples, such as blood, as compared with general RNAs on which various studies have been done so far, and are easily degraded by RNA degrading enzymes contained in biological samples.” See paragraph [0003]. And while the specification also states that microRNAs can be “used as markers in the diagnosis of cancer,” there is no disclosure of detection of any other class of disease other than a generic disclosure of dementia, nor the detection of particular types of cancer or other diseases (paragraphs [0003] and [0041]). However, it is impossible for one to extrapolate from the generic recitation of broad classes of microRNAs or how to use such microRNAs as predictors of the broad classes of cancer and dementia.
The prior art does not appear to offset the deficiencies of the instant specification. The prior art teaches the determination of microRNAs does not meet current demands of detection of abnormal miRNA expression in detection of cancers (Ye et al., 9 Journal of Pharmaceutical Analysis 217-226 (2019)) (abstract). Ye further discloses miRNA detection methods, such as nanomaterial-based miRNA detection, nucleic acid amplification techniques, SDA-based miRNA detection, and enzyme-free amplification (pages 219-224). However, Ye fails to disclose how to use miRNA detection for use as a disease or cancer/dementia marker.
Cissell et al. (394 Analytical and Bioanalytical Chemistry 1109-1116 (2009)) disclose that microRNAs can be linked to onset of cancer and other diseases based on miRNA expression levels (abstract). Cissell discloses that multiple detection methods are available and include “microarray technology, luminescence-based assays, electrochemical assays,” but notes that “there is still much work to be done regarding miRNA detection” (abstract). Cissell further discloses that miRNAs can be both upregulated or downregulated in cancer cells, depending on the miRNA and the type of cancer (page 1110, paragraph bridging columns 1 and 2). Cissell further discloses that miRNAs can play an important role in cardiovascular disease (page 110, paragraph bridging columns 1 and 2).
However, while both Ye and Cissell disclose the importance of miRNAs in diseases, including cancer, and disclose a variety of detection methods, neither provide a definitive method of detection of miRNAs. Nor does the prior art provide for detecting all miRNAs or how to determine which miRNAs are important in the diagnosis of the wide variety of diseases and cancers.
The description of the limited sources binding proteins is not sufficient to support the genus of such proteins. Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed.” (See Vas-Cath at page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is now is claimed." (See Vas-Cath at page 1116).
As discussed above, the skilled artisan cannot envision the method of broadly detecting microRNAs and using those microRNAs to detect all types of cancer and/or dementia, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation or identification. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18USPQ2d 1016. Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 1-13.
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.
Claims 1-13 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.
At claim 1, line 5; claim 8, line 2; and claim 9, line 2, it is not clear what is meant by the terms “preserving” and “preserved.” Is the preservation performed at a particular temperature, in a particular physical state, using any particular components, or for any particular length of time. The specification recites that the preservation of the mixed liquid or sample is performed without freezing. No other parameters are noted. Therefore, the metes and bounds of the claim are unclear.
Claims 2-8 and 10-13 depend from claim 1, and are therefore included in this rejection.
Claim 11 recites the limitation "the microarray analysis" in line 2. There is insufficient antecedent basis for this limitation in the claim.
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.
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 1-2, 6, and 8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hata et al. (396 Biochemical and Biophysical Research Communications 528-533 (2010), and cited in the Information Disclosure Statement filed August 31, 2023).
Regarding claim 1, Hata discloses that a whey fraction (a biological sample) is mixed with an acid to obtain a mixed liquid of the sample (Sections 2.2 and 2.9 and Figure 4). Hata discloses that the pH was adjusted and incubated (i.e., preserved) (Sections 2.2 and 2.9 and Figure 4). Hata discloses that microvesicles and microvesicle-derived miR-101, miR-1150, and miR-93 were collected and detected (Sections 2.2 and 2.9 and Figure 4).
Regarding claim 2, Hata discloses that the liquid sample was adjusted to pH 2.0 with hydrochloric acid, incubated (i.e., preserved) at 37 °C for 30 minutes, after which microvesicles and microvesicle-derived miRN-101, miR-150, and miR-93 were detected (sections 2.9 and 2.2 and Figure 4).
Regarding claim 6, Hata discloses that the pH is adjusted with hydrochloric acid (HCl) (Section 2.9).
Regarding claim 8, Hata discloses that the incubation (i.e., preservation) is performed for 30 minutes, which is less than 96 hours (Section 2.9).
Hata discloses each and every limitation of claims 1-2, 6, and 8, and therefore Hata anticipates claims 1-2, 6, and 8.
Claims 1-2, 5-6, 8-9, and 11-13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Löper et al. (U.S. Patent Application Publication No. 2017/0198279, published July 13, 2017, and cited in the Information Disclosure Statement filed August 31, 2023).
Regarding claim 1, Löper discloses that microRNAs can be isolated from various tissues and body fluids (paragraph [0002]). Löper discloses that a biological sample can be obtained and used to isolate and detect small RNA molecules, such as microRNAs (paragraph [0002]). Löper discloses mixing the biological sample with an acid to obtain a mixed liquid, incubating (i.e., preserving) the mixed liquid, collecting the microRNAs, and detecting the microRNAs (paragraphs [0002], [0018], [0029], and [0072]).
Regarding claim 2, Löper discloses that the mixed liquid pH can be pH 3.0 (paragraph [0035]).
Regarding claim 5, Löper discloses that the biological sample from which miRNAs can be isolated can be blood, plasma, or serum (paragraph [0023]).
Regarding claim 6, Löper discloses that the acid can be acetic acid or citric acid (paragraph [0073]).
Regarding claim 8, Löper discloses that the incubation of the acidified sample (i.e., preservation after acidification in the precipitation step) can take place for several hours at 4 °C (paragraph [0272]).
Regarding claim 9, Löper discloses that the incubation of the acidified sample (i.e., preservation after acidification in the precipitation step) can take place for several hours at 4 °C (paragraph [0272]).
Regarding claim 11, Löper discloses that the miRNA can be detected by a PCR array, which is interpreted as being a microarray analysis (paragraphs [0038]-[0053]). Löper discloses that the analysis can be a microarray analysis (paragraph [0142]).
Regarding claims 12-13, Löper discloses that the miRNAs can be used for disease screening, including cancer screening (paragraph [0140]).
Löper discloses each and every limitation of claims 1-2, 5-6, 8-9, and 11-13, and therefore Löper anticipates claims 1-2, 5-6, 8-9, and 11-13.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 3-4 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Löper et al. (U.S. Patent Application Publication No. 2017/0198279, published July 13, 2017, and cited in the Information Disclosure Statement filed August 31, 2023), as applied to claims 1-2, 5-6, 8-9, and 11-13 above, and in view of Kacian et al. (U.S. Patent No. 5,386,024, issued January 31, 1995, and cited in the Information Disclosure Statement filed August 31, 2023).
Regarding claim 1, Löper discloses that microRNAs can be isolated from various tissues and body fluids (paragraph [0002]). Löper discloses that a biological sample can be obtained and used to isolate and detect small RNA molecules, such as microRNAs (paragraph [0002]). Löper discloses mixing the biological sample with an acid to obtain a mixed liquid, incubating (i.e., preserving) the mixed liquid, collecting the microRNAs, and detecting the microRNAs (paragraphs [0002], [0018], [0029], and [0072]).
Regarding claim 2, Löper discloses that the mixed liquid pH can be pH 3.0 (paragraph [0035]).
Regarding claim 5, Löper discloses that the biological sample from which miRNAs can be isolated can be blood, plasma, or serum (paragraph [0023]).
Regarding claim 6, Löper discloses that the acid can be acetic acid or citric acid (paragraph [0073]).
Regarding claim 8, Löper discloses that the incubation of the acidified sample (i.e., preservation after acidification in the precipitation step) can take place for several hours at 4 °C (paragraph [0272]).
Regarding claim 9, Löper discloses that the incubation of the acidified sample (i.e., preservation after acidification in the precipitation step) can take place for several hours at 4 °C (paragraph [0272]).
Regarding claim 11, Löper discloses that the miRNA can be detected by a PCR array, which is interpreted as being a microarray analysis (paragraphs [0038]-[0053]). Löper discloses that the analysis can be a microarray analysis (paragraph [0142]).
Regarding claims 12-13, Löper discloses that the miRNAs can be used for disease screening, including cancer screening (paragraph [0140]).
Löper fails to disclose or suggest increasing the pH after incubation (i.e., preservation) and prior to collection of the miRNAs.
Regarding claim 1, Kacian discloses methods of obtaining a desired nucleic acid from a biological sample by acidifying the sample to render nucleases inactive, incubating (i.e., preserving) and raising the pH to render a protease less active (abstract). Kacian discloses that the method is particularly applicable to RNA molecules (column 1, lines 47-51).
Regarding claim 2, Kacian discloses that the acidification should bring the pH to between 1.0 and 4.0 (column 4, lines 15-30 and line 49 to column 5, line 4).
Regarding claims 3-4, Kacian discloses that the pH can be raised to greater than 6.0 (column 4, line 49 to column 5, line 4).
Regarding claim 5, Kacian discloses that the biological sample can be blood or other body fluids, including serum (column 5, lines 32-35 and Example 1).
Regarding claim 6, Kacian discloses that the pH can be lowered by addition of hydrochloric acid, acetic acid, or other acidic buffers (column 5, lines 36-54).
Regarding claim 8, Kacian discloses incubating the acidified sample for 5 minutes, which is less than 96 hours (Example 3).
Regarding claim 10, Kacian discloses raising the pH with a Tris base (Example 3).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to use Kacian’s method of first acidifying the biological sample and increasing the pH of Löper’s microRNA detection method because this will both reduce the activity of RNAses at acidic pH and reduce the activity of proteases at the higher pH. One of ordinary skill in the art would have been motivated to increase the pH of Löper’s biological sample according to Kacian because this will provide for obtaining a more pure microRNA by decreasing both nucleases and proteases.
Allowable Subject Matter
The prior art fails to disclose or suggest a method of detecting microRNAs where a biological sample is acidified by mixing with a homogeneous composition comprising a hydrochloride of a neutral amino acid, water, and an alcohol. In addition, the prior art fails to disclose or suggest that the biological sample is acidified in a semi-solid state at 23 °C.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Lekchnov et al. (499, Analytical Biochemistry 78-84 (2016)) disclose that microRNAs can be detected from biological samples, such as blood or plasma by mixing the sample with an acid, incubating (i.e., preserving) the resulting mixed liquid, collecting the microRNAs, and detecting the microRNAs (abstract and page 79, column 1, third full paragraph). Lekchnov discloses that the pH can be adjusted to pH 4.0 with octanoic acid (page 79, column 1, fourth full paragraph).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NANCY J LEITH whose telephone number is (313)446-4874. The examiner can normally be reached Monday - Thursday 8:00 AM - 6:30 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, NEIL HAMMELL can be reached at (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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NANCY J. LEITH
Primary Examiner
Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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