DETAILED ACTION
Election/Restrictions
Applicant’s election without traverse of Group I, claims 65-82, in the reply filed on October 7, 2025 is acknowledged. Claims 65-82 will be examined.
Information Disclosure Statement
The information disclosure statements filed on January 23, 2023, April 6, 2023, June 22, 2023, September 5, 2023, December 4, 2023, March 5, 2024, June 3, 2024, September 4, 2024, December 2, 2024, March 5, 2025, June 3, 2025, and October 7, 2025 contain 78 pages which include 1694 patent and non-patent literatures. However, most of these patent and non-patent literatures are unrelated to this instant application. Applicant should consider only to file patent and non-patent literatures related to this instant application such that the valuable time of the examiner should not be wasted.
Claim Objections
Claim 65 is objected to because of the following informality: “an analyte of interest” in step (e) should be “the analyte of interest”.
Claim 68 is objected to because of the following informality: “to its structure” should be “in its structure”.
Claim 72 is objected to because of the following informality: “at least 2 undesired nucleic acid” should be “at least 2 undesired nucleic acids”.
Appropriate correction is required.
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.
Scope of Enablement
Claims 65-82 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for performing steps (a) and (b) of claim 65, does not reasonably provide enablement for increasing the efficiency of capture of an analyte of interest in a biological sample using the methods recited in claims 65-82. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.”
The Nature of The Invention
The claims are drawn to a method for increasing the efficiency of capture of an analyte of interest in a biological sample. The invention is a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The Breadth of The Claims
Claims 65-82 encompass a method for increasing the efficiency of capture of an analyte of interest in a biological sample comprising: (a) contacting the biological sample with a substrate comprising a plurality of capture probes, wherein a capture probe of the plurality of capture probes comprises (i) a spatial barcode and (ii) a capture domain that specifically hybridizes to the analyte of interest; (b) contacting the biological sample with a plurality of blocker oligonucleotides, wherein a blocker oligonucleotide of the plurality of blocker oligonucleotides comprises (i) at least one non-natural nucleic acid and (ii) is substantially complementary to a sequence of an undesirable nucleic acid molecule in the biological sample; (c) hybridizing the blocker oligonucleotide to the undesirable nucleic acid molecule and the analyte of interest to the capture domain of the capture probe on the array; (d) extending the capture probe using the analyte of interest as a template to generate an extended capture probe; and (e) amplifying the extended capture probe, wherein the efficiency of capture of an analyte of interest is increased relative to a reference biological sample to which the plurality of blocker oligonucleotides has not been added.
Working Examples
The specification provides two examples (see paragraphs [0183] to [0185] and Figures 7A and 7B of US 2023/0279474 A1, which is US publication of this instant case). However, the specification provides no working example for increasing the efficiency of capture of an analyte of interest in a biological sample using the methods recited in claims 65-82.
The Amount of Direction or Guidance Provided and The State of The Prior Art
The specification provides two examples (see paragraphs [0183] to [0185] and Figures 7A and 7B of US 2023/0279474 A1, which is US publication of this instant case). However, the specification provides no working example for increasing the efficiency of capture of an analyte of interest in a biological sample using the methods recited in claims 65-82. Furthermore, there is no experimental condition and/or experimental data in the specification to support the claimed invention. During the process of the prior art search, the office does not find any prior art related to increase the efficiency of capture of an analyte of interest in a biological sample using the methods recited in claims 65-82.
Level of Skill in The Art, The Unpredictability of The Art, and The Quantity of Experimentation Necessary
While the relative skill in the art is very high (the Ph.D. degree with laboratory experience), there is no predictability whether the methods recited in claims 65-82 can be used for increasing the efficiency of capture of an analyte of interest in a biological sample.
Since the specification shows that “[R]eferring to FIG. 7A, in some instances, a blocker oligonucleotide 702 is designed to be complementary to a section of an undesirable target 703. In some instances, as shown in FIG. 7A, multiple blocker oligonucleotides 702 can be designed to target the same undesirable target 703. In some instances, the blocker oligonucleotide specifically binds (e.g., hybridizes) to an undesirable target 703. In some embodiments, the blocker oligonucleotide 702 comprises at least one non-natural nucleic acid (e.g., one or more LNAs)” and “[R]eferring to FIG. 7B, the methods include a biological sample 701 (e.g., a single cell, a tissue sample, etc.). In some instances, the biological sample is placed on a substrate 706
that includes a plurality of probes 705. In some instances, the sample is permeabilized using one or more of the permeabilization buffers or solutions disclosed herein. In some instances, a plurality of blocker oligonucleotides 702 are added to the biological sample. The plurality of blocker oligonucleotides 702 hybridize to an undesirable nucleic acid molecule (e.g., rRNA)
703 but does not hybridize to an analyte of interest 704. After blocker oligonucleotides 702
hybridize to the undesirable nucleic acid molecule 703, analytes of interest (e.g., 704) are captured by a probe 705 on the substrate 706 for analysis of the analyte (e.g., as disclosed herein)” (see paragraphs [0165] and [0171], and Figures 7A and 7B of US 2023/0279474 A1, which is US publication of this instant application), the specification clearly indicates that the plurality of blocker oligonucleotides hybridizes to an undesirable nucleic acid molecule but does not hybridize to an analyte of interest. Although claim 65 requires contacting the biological sample with a substrate comprising a plurality of capture probes, wherein a capture probe of the plurality of capture probes comprises (i) a spatial barcode and (ii) a capture domain that specifically hybridizes to the analyte of interest, contacting the biological sample with a plurality of blocker oligonucleotides, wherein a blocker oligonucleotide of the plurality of blocker oligonucleotides comprises (i) at least one non-natural nucleic acid and (ii) is substantially complementary to a sequence of an undesirable nucleic acid molecule in the biological sample, and hybridizing the blocker oligonucleotide to the undesirable nucleic acid molecule and the analyte of interest to the capture domain of the capture probe on the array, since claim 65 does not require that the analyte of interest is a nucleic acid, if the analyte of interest is a protein, it is unpredictable how the analyte of interest can hybridize with the capture probe such that that a hybridization complex comprising the capture probe and the analyte of interest cannot be formed, an extended capture probe cannot be generated by extending the capture probe on the first hybridization complex using the analyte of interest as a template, and the methods recited in claims 65-82 cannot be used for increasing the efficiency of capture of an analyte of interest in a biological sample. Furthermore, since claim 65 does not require that the plurality of blocker oligonucleotides hybridizes to the undesirable nucleic acid molecule but does not hybridize to the analyte of interest and it is known that a long nucleic acid probe can displace a short nucleic acid probe from a hybridization complex formed by a target nucleic acid and the short nucleic acid probe (see Figure 2A of Ding et al., Analytica Chimica Acta, 1242, 340810, 2023), if the analyte of interest is a nucleic acid, the plurality of blocker oligonucleotides is fully complementary to and hybridizes to the analyte of interest, and occupied whole length of the analyte of interest after the hybridization, and the length of each of the plurality of blocker oligonucleotides is longer than the length of the capture probe, the plurality of blocker oligonucleotides competes with the capture probe to hybridize with the analyte of interest such that a hybridization complex comprising the capture probe and the analyte of interest cannot be formed, an extended capture probe cannot be generated by extending the capture probe on the first hybridization complex using the analyte of interest as a template, and the methods recited in claims 65-82 cannot be used for increasing the efficiency of capture of an analyte of interest in a biological sample. In addition, since claim 66 does not require that the biological sample is fixed on a solid support, if the biological sample is in a solution, it is unpredictable how determining (i) the sequence of the spatial barcode or a complement thereof, and (ii) all or a portion of the sequence of the analyte of interest from the biological sample can identify the location of the analyte of interest in the biological sample.
Case law has established that “(t)o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation’.” In re Wright 990 F.2d 1557, 1561. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) it was determined that “[T]he scope of the claims must bear a reasonable correlation to the scope of enablement provided by the specification to persons of ordinary skill in the art”. The amount of guidance needed to enable the invention is related to the amount of knowledge in the art as well as the predictability in the art. Furthermore, the Court in Genentech Inc. v Novo Nordisk 42 USPQ2d 1001 held that “[I]t is the specification, not the knowledge of one skilled in the art that must supply the novel aspects of the invention in order to constitute adequate enablement”.
In view of above discussions, the skilled artisan will have no way to predict the experimental results. Accordingly, it is concluded that undue experimentation is required to make the invention as it is claimed. These undue experimentation at least includes to test whether the methods recited in claims 65-82 can be used for increasing the efficiency of capture of an analyte of interest in a biological sample.
Conclusion
In the instant case, as discussed above, the level of unpredictability in the art is high, the specification provides one with no guidance that leads one to claimed methods. One of skill in the art cannot readily anticipate the effect of a change within the subject matter to which the claimed invention pertains. Thus given the broad claims in an art whose nature is identified as unpredictable, the unpredictability of that art, the large quantity of research required to define these unpredictable variables, the lack of guidance provided in the specification, the absence of any working example related to claimed invention and the no teaching in the prior art balanced only against the high skill level in the art, it is the position of the examiner that it would require undue experimentation for one of skill in the art to perform the method of the claim as broadly written.
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 65-82 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 65 is rejected as vague and indefinite in view of step (b) because it is unclear that contacting the biological sample with a plurality of blocker oligonucleotides is happened in the substrate after step (a) or is happened in a solution after step (a) or before step (a). Please clarify.
Claim 65 is rejected as vague and indefinite in view of steps (c) and (d) because these steps do not make sense. Do these steps mean “(c) hybridizing the blocker oligonucleotide to the undesirable nucleic acid molecule and the analyte of interest on the substrate and producing a first hybridization complex formed by the capture probe and the analyte of interest and a second hybridization formed by the blocker oligonucleotide and the undesirable nucleic acid molecule; (d) generating an extended capture probe by extending the capture probe on the first hybridization complex using the analyte of interest as a template”? Please clarify.
Claim 65 recites the limitation “the array” in step (c) of the claim. There is insufficient antecedent basis for this limitation in the claim because there is no phrase “an array” in step (a) or (b). Please clarify.
Claim 79 recites the limitation “the hybridization products of the plurality of blocker oligonucleotide and undesirable nucleic acid molecules” in the claim. There is insufficient antecedent basis for this limitation in the claim because there is no phrase “hybridization products of the plurality of blocker oligonucleotide and undesirable nucleic acid molecules” in claim 65. Please clarify.
Claim 80 is rejected as vague and indefinite Since claim 80 does not require that the biological sample is a cell, it is unclear why the biological sample is required to be permeabilized in the claim. Please clarify.
Conclusion
No claim is allowed.
Papers related to this application may be submitted to Group 1600 by facsimile transmission. Papers should be faxed to Group 1600 via the PTO Fax Center. The faxing of such papers must conform with the notices published in the Official Gazette, 1096 OG 30 (November 15, 1988), 1156 OG 61 (November 16, 1993), and 1157 OG 94 (December 28, 1993)(See 37 CAR § 1.6(d)). The CM Fax Center number is (571)273-8300.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Frank Lu, Ph.D., whose telephone number is (571)272-0746. The examiner can normally be reached on Monday-Friday from 9 A.M. to 5 P.M.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Dr. Anne Gussow, Ph.D., can be reached on (571)272-6047.
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/FRANK W LU/Primary Examiner, Art Unit 1683 December 12, 2025