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 of Group II (claims 49-53, 58, 61-65, 67-68, 70-73) in the reply filed on 12/01/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1, 25, and 74 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/01/2025.
Claims Status
Claims 2-24, 26-48, 54-57, 59-60, 66, 69, 75-99 is/are cancelled. Claims 1, 25, 49-53, 58, 61-65, 67-68, 70-74 is/are currently pending with claims 1, 25, 74 withdrawn. Claims 49-53, 58, 61-65, 67-68, 70-73 is/are under examination.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Information Disclosure Statement
The information disclosure statement filed 11/18/2022 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered. References not provided but cited in the IDS have been struck through in the annotated IDS mailed with this office action.
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they do not include the following reference sign(s) mentioned in the description: “Section 1” and “Section 2” in Figs. 7A-7B (see pages 7-8). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Figs. 7A and 7B each have two panels: 7A has panels titled “PUF3.2 (HCT116)” and “PUF3.5 (HCT116)”; 7B has panels titled “PUF4.1 (HeLa)” and “PUF4.2 (HeLa)”. Identification of which panel is “Section 1” or “Section 2” by associating or replacing “Section 1” or “Section 2” with the corresponding panel label present in the drawing will be sufficient to overcome this objection.
Claim Rejections - 35 USC § 112
112(b):
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 50, 65 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 50 recites that “the genetic barcode comprises more than four nucleotide barcodes.” The specification does not describe structural or functional differences between a “genetic barcode” and a “nucleotide barcode”. It is unclear in what way a genetic barcode, consisting of nucleotides and comprising four or more barcode sequences, differs from a genetic barcode which comprises more than four nucleotides, wherein each nucleotide could be considered a nucleotide barcode (as one nucleotide is the shortest unit of a nucleotide sequence). However, the specification does, on multiple occasions, describe a four-nucleotide barcode or a barcode comprising more than four nucleotides (page 2 line 17; page 18 lines 3-12; page 20 line 6; page 22 lines 18-27). It is thus unclear what the structural or functional requirements are by which a sequence may be determined to be a “genetic barcode” or a “nucleotide barcode”, and thus it is unclear what sequences fulfill the requirements of claim 50.
Claim 65 recites a “TdT” (line 2). The specification does not disclose a “TdT” nor what structure or process “TdT” refers to. A search of “TdT” did not produce results clearly applicable to the pending claims. An artisan would not be able to determine what structure or process is required by claim 65 in order to “enrich” insertion mutations, rendering claim 65 unclear and indefinite. Due to this indefiniteness and the central role of this “TdT” in claim 65, claim 65 cannot be further examined.
112(a):
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.
Claim 73 is 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.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V, v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Eiees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641,1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F. 2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it”).
According to the MPEP § 2163, "The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. 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. See AbbVie Deutsch land GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.")."
Claim 73 recites a barcode-indel combination which “is impossible to replicate”. For a sequence to be impossible to replicate, there must be no possible way to replicate the sequence—hence, “impossible”. However, the applicants state in the specification that replication is possible through DNA synthesis (page 38 lines 2-10). While DNA synthesis may be expensive, it is not impossible. Therefore, the applicants have not described in their disclosure a barcode-indel sequence which is impossible to replicate. Claim 73 is therefore rejected for lack of written description.
Claim Rejections - 35 USC § 102
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 49-53, 58, 61-64, 71-72 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Roy (2018, of record).
Regarding claim 49, Roy teaches a method of manufacturing a cell line, comprising the steps of integrating a genetic barcode into a genome of a cell and integrating an indel mutation into the genome of the cell adjacent to the genetic barcode (Fig. 1; pages 513, 516 “designed guide-donor pairs to target…1,629 out of 3,548 indels”, page 512 “we use MAGESTIC to introduce thousands of single-nucleotide polymorphisms (SNPs) and small indels”). As described by the instant specification, “adjacent” can mean “within about 1000 nucleotides” (page 19 lines 11-17).
Regarding claim 50, Roy teaches that the genetic barcode sequence comprises at least four nucleotides (the genetic barcode sequence is 31 nucleotides long, page 513; see rejection of claim 50 under 35 USC 112(b), a sequence which comprises at least four nucleotides can be considered to comprise at least four nucleotide barcodes).
Regarding claim 51, Roy teaches a library of 2 x 106 barcodes (page 513).
Regarding claims 52-53, Roy teaches that the genetic barcode is integrated into the genome of the cell via CRISPR-mediated homologous recombination (Fig. 1; page 513).
Regarding claim 58, Roy teaches that the indel mutation is within 1000 bp from the genetic barcode (“Online Methods” page 1, the guide-donor sequences comprise 20 codons, and thus any mutation within the guide-donor sequence is within 60 nucleotides of the barcode).
Regarding claims 61-64, Roy teaches that 30% of the guide-donor-barcode sequences are integrated by NHEJ, thereby introducing random indel mutations of random lengths (page 513).
Regarding claims 71-72, Roy teaches that the barcode is 31 nucleotides long and is unique and distinct, allowing for single-cell identification (page 513; Fig. 1). Moreover, a 31-mer sequence has 4.61x1018 possible permutations, therefore able to uniquely identify 4.61x1018 different cells.
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.
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.
Claim(s) 49-53, 58, 61-64, 67-68, 71-72 is/are rejected under 35 U.S.C. 103 as being unpatentable over Roy (2018), in view of Gill (US 20170369870 A1).
Regarding claim 49, Roy teaches a method of manufacturing a cell line, comprising the steps of integrating a genetic barcode into a genome of a cell and integrating an indel mutation into the genome of the cell adjacent to the genetic barcode (Fig. 1; pages 513, 516 “designed guide-donor pairs to target…1,629 out of 3,548 indels”, page 512 “we use MAGESTIC to introduce thousands of single-nucleotide polymorphisms (SNPs) and small indels”). As described by the instant specification, “adjacent” can mean “within about 1000 nucleotides” (page 19 lines 11-17).
Regarding claim 50, Roy teaches that the genetic barcode sequence comprises at least four nucleotides (the genetic barcode sequence is 31 nucleotides long, page 513; see rejection of claim 50 under 35 USC 112(b), a sequence which comprises at least four nucleotides can be considered to comprise at least four nucleotide barcodes).
Regarding claim 51, Roy teaches a library of 2 x 106 barcodes (page 513).
Regarding claims 52-53, Roy teaches that the genetic barcode is integrated into the genome of the cell via CRISPR-mediated homologous recombination (Fig. 1; page 513).
Regarding claim 58, Roy teaches that the indel mutation is within 1000 bp from the genetic barcode (“Online Methods” page 1, the guide-donor sequences comprise 20 codons, and thus any mutation within the guide-donor sequence is within 60 nucleotides of the barcode).
Regarding claims 61-64, Roy teaches that 30% of the guide-donor-barcode sequences are integrated by NHEJ, thereby introducing random indel mutations of random lengths (page 513).
Regarding claims 71-72, Roy teaches that the barcode is 31 nucleotides long and is unique and distinct, allowing for single-cell identification (page 513; Fig. 1). Moreover, a 31-mer sequence has 4.61x1018 possible permutations, therefore able to uniquely identify 4.61x1018 different cells.
However, Roy teaches that the barcoding system is expressed in yeast, not in mammalian cells (“Online Methods: Yeast strains and media”).
Gill teaches that genetic barcoding systems can be expressed in mammalian (and specifically, human) cells.
Regarding claims 67-68, Gill teaches a nucleotide barcode system integrated into a cell genome (claims 1, 9-10; paragraph [0103]). Gill further teaches that these nucleotide barcode systems can be expressed in any cell in which a CRISPR nuclease can be active, including a human cell (paragraph [0053]). It would have been obvious to an artisan at the time of filing that the methods and compositions used to integrate and express the promoter-donor-barcode system of Roy could be adapted for use in human cells, in order to provide a mechanism for single-cell identification, as enabled in yeast by Roy.
Claim(s) 70 is/are rejected under 35 U.S.C. 103 as being unpatentable over Roy (2018) and Gill (US 20170369870 A1) as applied to claim 49 above, and further in view of Sadelain (2012).
The limitations of instant claim 49 are rendered obvious by the teachings of Roy and Gill, as described above.
However, Roy and Gill do not teach integration of a barcoded nucleotide sequence into a genomic safe harbor locus.
Sadelain teaches genomic safe harbor loci.
Regarding claim 70, Sadelain teaches that it is beneficial to integrate foreign DNA into a safe harbor locus in a cell genome, as the disruption of these loci by the integration of the foreign DNA does not affect cellular function or survival (page 51).
As described above, Roy teaches that genomic barcoding can be used to identify individual cells, and Gill teaches that genomic barcoding can be used in human cells. It would have been obvious to an artisan, motivated to use the genomic barcoding system of Roy to uniquely identify individual human cells, as Gill teaches is possible, to integrate the genomic barcoding system of Roy into a genomic safe harbor locus in the human cells, in order to ensure that proper functioning and survival of the human cells are maintained.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AFRICA M MCLEOD whose telephone number is (703)756-1907. The examiner can normally be reached Mon-Fri 9:00AM-6:00PM EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached on (571) 272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
For those applications where applicant wishes to communicate with the examiner via Internet communications, e.g., email or video conferencing tools, the following is a sample authorization form which may be used by applicant:
"Recognizing that Internet communications are not secure, I hereby authorize the USPTO to communicate with the undersigned and practitioners in accordance with 37 CFR 1.33 and 37 CFR 1.34 concerning any subject matter of this application by video conferencing, instant messaging, or electronic mail. I understand that a copy of these communications will be made of record in the application file."
To facilitate processing of the internet communication authorization or withdraw of authorization, the Office strongly encourages use of Form PTO/SB/439, available at www.uspto.gov/patent/patents-forms. The form may be filed via EFS-Web using the document description Internet Communications Authorized or Internet Communications Authorization Withdrawn to facilitate processing. See MPEP 502.03(II).
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/AFRICA M MCLEOD/ Examiner, Art Unit 1635
/KIMBERLY CHONG/ Primary Examiner, Art Unit 1636