DETAILED ACTION
Election/Restrictions
Applicant’s election without traverse of species (2) (at least two of the plurality of control particle oligonucleotides comprises different control barcode sequences, see claim 422), species (3) (said determining the at least one characteristic of the one or more cells using the characteristics of the plurality of barcoded control oligonucleotides in the sequencing data comprises: determining the number of cell label sequences with distinct sequences associated with the plurality of barcoded control oligonucleotides in the sequencing data; and determining the number of the one or more cells using the number of cell label sequences with distinct sequences associated with the plurality of barcoded control oligonucleotides, see claims 426 and 427), and species (6) (determining single cell capture efficiency based on the ratio of the number of the one or more cells determined and the number of the plurality of cells, see claim 427) in the reply filed on June 9, 2026 is acknowledged. Claims 405, 406, 422, 426, 427, 432, 437, 439, 443, 450, 451, 454, 468, 470, 471, and 475 will be examined.
Information Disclosure Statement
IDS filed on December 6, 2022, September 25, 2025, and June 9, 2026 contains 111 pages and 2431 patent and non-patent literatures. However, since most of these patent and non-patent literatures are unrelated to this application, applicant should only file patent and non-patent literatures related to this application such that valuable time of the examiner will not be wasted.
Specification
The disclosure is objected to because of the following informalities: (1) since case 15/715,028 has been patented, applicant is required to update this information in paragraph [0001] of the specification; (2) page 152 of the specification describes cellular mRNA 530 in Figure 7. However, there is no cellular mRNA 530 in Figure 7; (3) pages 152 and 153 of the specification describes items control particles 740, control particle oligonucleotides 725, cells 710, droplets 745a and 745, hydrogels 720a and 720b, genomic DNA or cellular mRNA 730, and cellular mRNA 530. However, there are no these items in Figure 8; and (4) page 241 of the specification contains a nucleotide sequence having more than 10 nucleotides. However, there is no SEQ ID No. for this nucleotide sequence in page 241.
Appropriate correction is required.
Claim Objections
Claim 405 is objected to because of the following informalities: (1) “the control oligonucleotides” in barcoding step should be ““the control oligonucleotide”; and (2) “wherein at least two barcodes of the plurality of barcodes comprise an identical cell label sequence” should be “wherein the cell label sequence of each of the at least two barcodes of the plurality of barcodes is identical”.
Claim 422 is objected to because of the following informality: “the control barcode sequences of at least two of the plurality of control particle oligonucleotides are identical” should be “the control barcode sequence of each of at least two of the plurality of control particle oligonucleotides is identical”.
Claim 426 is objected to because of the following informalities: (1) “determining the at least one characteristic of the one or more cells” should be “said determining the at least one characteristic of the one or more cells”; (2) “cell labeled sequences” should be “the cell labeled sequence”; and (3) “distinct sequences” in line 6 should be “the distinct sequences”.
Claim 468 is objected to because of the following informality: “the barcode sequences of the barcodes” should be “the barcode sequence of each of the barcodes”.
Claim 470 is objected to because of the following informality: this claim should be deleted since claim 405 has all limitations of this claim.
Claim 471 is objected to because of the following informality: “wherein barcoding the plurality of control oligonucleotides using the plurality of barcodes comprises: contacting the plurality of barcodes with control oligonucleotides of the plurality of control compositions to generate barcodes hybridized to the control oligonucleotides; and extending the barcodes hybridized to the control oligonucleotides to generate the plurality of barcoded control oligonucleotides” should be “wherein said barcoding the control oligonucleotide using the plurality of barcodes comprises: contacting the plurality of barcodes with the control oligonucleotide of each of the plurality of control compositions to generate barcodes hybridized to the control oligonucleotide; and extending the barcodes hybridized to the control oligonucleotide to generate the plurality of barcoded control oligonucleotides”.
Claim 475 is objected to because of the following informality: “obtaining the sequencing data” should be “said obtaining the sequencing data of the plurality of barcoded control oligonucleotides”.
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 405, 406, 422, 426, 427, 432, 437, 439, 443, 450, 451, 454, 468, 470, 471, and 475 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 contacting one or more cells of a plurality of cells with a control composition of a plurality of control compositions in vitro, does not reasonably provide enablement for determining at least one any kind of characteristic of the one or more cells using at least one any kind of characteristic of the plurality of barcoded control oligonucleotides in the sequencing data using the methods recited in claims 405, 406, 422, 426, 427, 432, 437, 439, 443, 450, 451, 454, 468, 470, 471, and 475. 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 sequencing control. 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 405, 406, 422, 426, 427, 432, 437, 439, 443, 450, 451, 454, 468, 470, 471, and 475 encompass a method for sequencing control, comprising: contacting one or more cells of a plurality of cells with a control composition of a plurality of control compositions, wherein a cell of the plurality of cells comprises a plurality of targets and a plurality of protein targets, wherein each of the plurality of control compositions comprises a protein binding reagent associated with a control oligonucleotide, wherein the protein binding reagent is capable of specifically binding to at least one of the plurality of protein targets, and wherein the control oligonucleotide comprises a control barcode sequence and a pseudo-target region comprising a sequence substantially complementary to the target-binding region of at least one of the plurality of barcodes; barcoding the control oligonucleotides using a plurality of barcodes to create a plurality of barcoded control oligonucleotides, wherein each of the plurality of barcodes comprises a cell label sequence, a barcode sequence, and a target-binding region, wherein the barcode sequences of at least two barcodes of the plurality of barcodes comprise different sequences, and wherein at least two barcodes of the plurality of barcodes comprise an identical cell label sequence; obtaining sequencing data of the plurality of barcoded control oligonucleotides; determining at least one any kind of characteristic of the one or more cells using at least one any kind of characteristic of the plurality of barcoded control oligonucleotides in the sequencing data.
Working Examples
The specification provides 6 working example (see pages 100-106 of US 2023/ 0125113A1, which is US publication of this instant case). However, the specification provides no example for determining at least one any kind of characteristic of the one or more cells using at least one any kind of characteristic of the plurality of barcoded control oligonucleotides in the sequencing data using the methods recited in claims 405, 406, 422, 426, 427, 432, 437, 439, 443, 450, 451, 454, 468, 470, 471, and 475.
The Amount of Direction or Guidance Provided and The State of The Prior Art
The specification provides 6 working example (see pages 100-106 of US 2023/ 0125113A1, which is US publication of this instant case). However, the specification provides no example for determining at least one any kind of characteristic of the one or more cells using at least one any kind of characteristic of the plurality of barcoded control oligonucleotides in the sequencing data using the methods recited in claims 405, 406, 422, 426, 427, 432, 437, 439, 443, 450, 451, 454, 468, 470, 471, and 475. 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 examiner has not found any prior art which is related to determine at least one any kind of characteristic of the one or more cells using at least one any kind of characteristic of the plurality of barcoded control oligonucleotides in the sequencing data using the methods recited in claims 405, 406, 422, 426, 427, 432, 437, 439, 443, 450, 451, 454, 468, 470, 471, and 475.
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 at least one any kind of characteristic of the one or more cells can be determined using at least one any kind of characteristic of the plurality of barcoded control oligonucleotides in the sequencing data using the methods recited in claims 405, 406, 422, 426, 427, 432, 437, 439, 443, 450, 451, 454, 468, 470, 471, and 475.
Although claim 405 requires contacting one or more cells of a plurality of cells with a control composition of a plurality of control compositions, wherein a cell of the plurality of cells comprises a plurality of targets and a plurality of protein targets, wherein each of the plurality of control compositions comprises a protein binding reagent associated with a control oligonucleotide, wherein the protein binding reagent is capable of specifically binding to at least one of the plurality of protein targets, and wherein the control oligonucleotide comprises a control barcode sequence and a pseudo-target region comprising a sequence substantially complementary to the target-binding region of at least one of the plurality of barcodes, barcoding the control oligonucleotides using a plurality of barcodes to create a plurality of barcoded control oligonucleotides, wherein each of the plurality of barcodes comprises a cell label sequence, a barcode sequence, and a target-binding region, wherein the barcode sequences of at least two barcodes of the plurality of barcodes comprise different sequences, and wherein at least two barcodes of the plurality of barcodes comprise an identical cell label sequence, and obtaining sequencing data of the plurality of barcoded control oligonucleotides, since claim 405 does not require contacting the control compositions with a plurality of barcodes, if the control compositions do not contact with a plurality of barcodes, it is unpredictable how a plurality of barcoded control oligonucleotides can be created. Furthermore, it is known that macromolecules such as proteins, polysaccharides, and nucleic acids are simply too large and too charged or polar to pass through biological membrane (see “large Molecules Cross Membranes via vesicles”). Since claim 405 does not require that one or more cells of a plurality of cells are permeabilized cells and a plurality of barcoded control oligonucleotides can be created without the one or more cells of the plurality of cells in claim 405 when the control compositions contact with a plurality of barcodes, if one or more cells of a plurality of cells have complete cell membranes, a protein binding reagent associated with a control oligonucleotide of each of the plurality of control compositions cannot enter the one or more cells and cannot bind to one of the plurality of protein targets such that it is unpredictable how at least one any kind of characteristic of the one or more cells such as shapes of the one or more cell can be determined using at least one characteristic of the plurality of barcoded control oligonucleotides in the sequencing data such as the lengths of the plurality of barcoded control oligonucleotides as recited in claims 405, 406, 422, 432, 437, 439, 443, 450, 451, 454, 468, 470, 471, and 475 and how at least one any kind of characteristic of the one or more cells such as shapes of the one or more cell can be determined by only determining the number of cell label sequences with distinct sequences associated with the plurality of barcoded control oligonucleotides in the sequencing data and determining the number of the one or more cells using the number of cell label sequences with distinct sequences associated with the plurality of barcoded control oligonucleotides as recited in claim 426. Since at least one characteristic of the one or more cells can include a shape of a cell or a size of a cell or a weight of a cell or a response of a cell to a compound and claim 405 does not indicate that at least one characteristic of the one or more cells is what kind of characteristic and at least one characteristic of the plurality of barcoded control oligonucleotides in the sequencing data is what kind of characteristic, it is unpredictable how at least one any kind of characteristic of the one or more cells such as sizes of the one or more cell can be determined using at least one characteristic of the plurality of barcoded control oligonucleotides in the sequencing data such as the nucleotide sequences of the plurality of barcoded control oligonucleotides as recited in claims 405, 406, 422, 432, 437, 439, 443, 450, 451, 454, 468, 470, 471, and 475 and how at least one any kind of characteristic of the one or more cells such as sizes of the one or more cell can be determined by only determining the number of cell label sequences with distinct sequences associated with the plurality of barcoded control oligonucleotides in the sequencing data and determining the number of the one or more cells using the number of cell label sequences with distinct sequences associated with the plurality of barcoded control oligonucleotides as recited in claim 426. In addition, although the specification shows that “[C]apture efficiency can be determined for control particle oligonucleotides with different abundance. Normalization can be performed based on the capture efficiency of control particle oligonucleotides with two or more control barcode sequences” and “use of the functionalized control particles to determine capture
Efficiency” (see paragraphs [0536] and [0887] of US 2023/0125113A1, which is US publication of this instant case), since the specification does not indicate how the functionalized control particles is used to determine capture efficiency and claims 405 and 426 do not indicate how a single cell from the one or more cells of the plurality of the cell is captured, it is unclear how single cell capture efficiency can be determined based on the ratio of the number of the one or more cells determined and the number of the plurality of cells as recited in claim 427.
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 at least one any kind of characteristic of the one or more cells can be determined using at least one any kind of characteristic of the plurality of barcoded control oligonucleotides in the sequencing data using the methods recited in claims 405, 406, 422, 426, 427, 432, 437, 439, 443, 450, 451, 454, 468, 470, 471, and 475.
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 439, 451, and 475 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 439 recites the limitation “the plurality of binding targets” in the claim. There is insufficient antecedent basis for this limitation in the claim because there is no phrase “a plurality of binding targets” in claim 405. Please clarify.
Claim 451 is rejected as vague and indefinite. Since clam 405 requires that a protein binding reagent of each of the plurality of control compositions is associated with a control oligonucleotide while claim 450 requires that a second protein binding reagent of the plurality of control compositions is not associated with the control oligonucleotide, the protein binding reagent and the second protein binding reagent must be different. Thus, it is unclear why the protein binding reagent and the second protein binding reagent in claim 451 can be identical. Please clarify.
Claim 475 recites the limitations “claim 473” and “the plurality of amplicons” in the claim. There is insufficient antecedent basis for these limitations in the claim because claim 473 has been canceled and there is no phrase “a plurality of amplicons” in claim 405. Please clarify.
Conclusion
No claim is allowed.
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 Monday to Friday, 9 AM to 5 PM.
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/FRANK W LU/Primary Examiner, Art Unit 1683 July 24, 2026
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