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 .
Detailed Action
This action is in response to the papers filed October 1, 2025.
Claim Amendments
Applicant’s amendment to the claims filed 10/01/2025 is acknowledged.
Claims 2, 12-13, 21-26 have been cancelled.
Claims 27-28 are newly added.
Claims 1 and 14 are amended.
Claims 1, 3-11, 14-20, 27-28 are pending.
Claims 4-5, 7-11, 16-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species/invention.
Claims 1, 3, 6, 14-15, 27-28 are under examination.
Election/Restrictions
The following is a summary of the restriction/election requirements in the application. See Requirement for Restriction/Election mailed 10/13/2023.
In the reply filed 12/12/2023, applicant elected without traverse:
the species of introducing foreign DNA into a targeted genome with homologous recombination of one of a 5'-end or a 3'-end of the foreign DNA and non-homologous recombination of the other end when double-strand breaks of a targeted genomic DNA occur, as the means of introducing foreign DNA into a genome; and
the species of a T cell, as the cell type that is genetically modified.
Accordingly, claims 4-5, 7-11, 16-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/12/2023.
Priority
The instant application 17/042,819 was filed on 09/28/2020. This application is a national stage of international application PCT/JP2019/013602 filed 03/28/2019, claiming priority based on Japanese patent application JP2018-066174 filed 03/29/2018.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. While a certified copy of the foreign patent application is provided with the instant application, a certified English translation of said foreign patent application has not been provided.
Withdrawal of Prior Rejections/Objections
Rejections and/or objections not reiterated from the previous Office action mailed 05/02/2025 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
In particular, in view of the most recent claim amendments, applicant’s traversal of the previous rejections under 35 U.S.C. 102, for anticipation over the “Basiri” reference, and 35 U.S.C. 112(a), for failing to comply with the written description requirement, are found persuasive. Accordingly, said rejections have been withdrawn.
Claim Interpretation
Page 21, lines 2-3, of the specification defines the claim term “non-homologous recombination” as meaning “non-homologous end joining”.
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.
Claims 1, 3, 6, 14-15, 27-28 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/096041 A1 to Corn et al.; in view of WO 2016/164356 A1 to Porteus et al.; Basiri et al. (2016) "The convenience of single homology arm donor DNA and CRISPR/Cas9-nickase for targeted insertion of long DNA fragment" Cell Journal (Yakhteh), 18(4), 532-539; and Ferrari et al. (2021) “Gene therapy using haematopoietic stem and progenitor cells” Nature Reviews Genetics, 22(4), 216-234 [evidentiary reference].
This rejection is newly applied, necessitated by amendment. A response to applicant’s traversal follows this rejection.
This rejection is directed to obviousness of the claims over the Corn, Porteus and Basiri disclosures. The Ferrari disclosure is cited as an evidentiary reference to show that lymphocytes are a cell type used for treating severe combined immunodeficiency.
Claims 1 and 5 of the Corn disclosure recite a method of editing genomic DNA of a eukaryotic cell comprising a step of introducing into a cell an asymmetric donor DNA molecule having a 5’ homology arm and a 3’ homology arm, wherein the 3’ homology arm is shorter than the 5’ homology arm, the 3’ homology arm is 20-50 nucleotides in length, and the 5’ homology arm is 40-200 nucleotides in length.
Claim 1 of the Corn disclosure further recites that the asymmetric donor DNA is introduced with a guide RNA and a Cas9 protein, and claims 2-3 of the Corn disclosure recite that the Cas9 protein cleaves the non-target strand and the target strand of the genomic DNA. Corn further discloses that the Cas9 protein generates a double stranded break (DSB). See, e.g., paragraphs 3, 206, 219-220.
Corn discloses that the donor DNA molecule may be introduced into a cell in linear form (par. 281), which means the donor DNA molecule comprises a 5’-end and a 3’-end as instantly claimed. Corn further discloses that the eukaryotic cell is a lymphocyte (par. 289), which is a “blood cell” (as instantly claimed in claim 3), a “differentiated cell” (as instantly claimed in claim 27), and a “bone marrow cell” (as instantly claimed in claim 28).
Corn does not disclose the donor DNA molecule possesses the same ranges for the lengths of the homology arms as found in the instantly claimed invention.
First, claims 1 and 14 of the instantly claimed invention recite that the long homology arm has a length of 50 nucleotides or more, and dependent claims 6 and 15 recite that the long homology arm has a length of less than 500 nucleotides. Accordingly, dependent claims 6 and 15 require the “second end” to comprise a homology arm length of 50-499 nucleotides.
Where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05. In this case, claim 5 of the Corn disclosure recites that the long homology arm has a length of 40-200 bp, which substantially overlaps with both the range of 50 nucleotides or more, as instantly claimed in claims 1 and 14, and the range of 50-499 nucleotides, as instantly claimed in dependent claims 6 and 15. Moreover, in the specification, Corn discloses that the long homology arm has a length of 50-75 bp, 75-100 bp, 100-125 bp, 125-150 bp, 150-175 bp or 175-200 bp, which lies inside the instantly claimed range of claims 1 and 14, and that of dependent claims 6 and 16.
For these reasons, the instantly claimed ranges of 50 nucleotides or more (claims 1 and 14) and 50-499 nucleotides (dependent claims 6 and 15), for the homology arm length of the “second end” of the donor DNA molecule, would have been prima facie obvious over the ranges found in the Corn disclosure.
Second, claims 1 and 14 recite that the short homology arm has a length of less than 10 nucleotides, or there is no homology arm on the first end of the donor DNA molecule. Accordingly, the “first end” of the donor DNA molecule has a homology arm length of 0-9 nucleotides.
Claim 1 of the Corn disclosure recites that the short homology arm has a length of 20-50 bp, and paragraph 7 of the Corn disclosure discloses a narrower range of 20-25 bp. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). In this case, one of ordinary skill in the art would have understood that the homology arms mediate integration of the donor DNA molecule into the target site of the host genome. Therefore, the ordinary skilled artisan would have been led to optimize through routine experimentation the homology arm length in order to improve the editing of a target site in the host genome.
In addition, prior to the effective filing date of the instantly claimed invention, Porteus discloses methods of genome editing with a donor DNA molecule having homology arms (par. 7, 91), wherein the homology arms may be 10 bp or more (par. 126); and Basiri discloses a donor DNA molecule having only a single homology arm, i.e., one flank has a homology arm length of 0 nucleotides (Abstract; pg. 532-533; Figure 1A). A range can be disclosed in multiple prior art references instead of in a single prior art reference depending on the specific facts of the case. Iron Grip Barbell Co., Inc. v. USA Sports, Inc., 392 F.3d 1317, 1322, 73 USPQ2d 1225, 1228 (Fed. Cir. 2004). In this case, in view of Porteus, one of ordinary skill in the art would have expected homology arms having a length as small as 10 nucleotides to be suitable for genome editing with a donor DNA molecule; and, in view of Basiri, one of ordinary skill in the art would have expected a DNA donor molecule having only a single homology arm, i.e., one flank has a homology arm length of 0 nucleotides, to be suitable for genome editing with a donor DNA molecule. Therefore, Porteus and Basiri, considered together, suggest a homology arm length of 0-10 nucleotides
For these reasons, the instantly claimed ranges of 0-9 nucleotides, for the homology arm length of the “first end” of the donor DNA molecule, would have been prima facie obvious over the ranges found in the cited prior art references (Corn, Porteus and Basiri).
In sum, the only structural differences between the Corn disclosure and the instantly claimed invention are found in the homology arm lengths of the flanking regions of the donor DNA molecule. However, Corn provides the general condition of a donor DNA molecule having a short homology arm on a first end and a long homology on a second end, as instantly claimed. Therefore, absent a secondary consideration or evidence of criticality for the instantly claimed homology arm lengths, the claimed ranges for the lengths of the homology arms would have been prima facie obvious over the prior art, for the reasons outlined above.
Corn does not expressly disclose that homologous-directed recombination (“homologous recombination”) occurs at one of the 3’ or 5’ ends of the donor DNA and non-homologous end joining (“non-homologous recombination”) occurs at the other end, when double-strand breaks of a targeted genomic DNA occur, as functionally claimed by instant claims 1 and 14.
MPEP 2111.04, section I, instructs that claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. In this case, the recitation that “homologous recombination” occurs at one of the 3’ or 5’ ends of the donor DNA and “non-homologous recombination” occurs at the other end indicates an intended result or functional property which naturally flows from performing the process steps positively recited in the claims and does not clearly limit the claims to a particular structure or manipulative action. A recitation of an intended result or functional property of the claimed invention must result in a structural or manipulative difference between the claimed invention and the cited prior art in order to patentably distinguish the claimed invention from the cited prior art. If the prior art structure is capable of performing the intended result, or if the functional property naturally flows from the cited prior art structure, then the cited prior art reads on the intended result or functional property recitation. There is no requirement that the cited prior art expressly teach or suggest the intended result or functional property recitation.
As outlined above, the structural features and manipulative actions positively recited by the claims would have been prima facie obvious over the cited prior art. In particular, a donor DNA construct having 3’ and 5’ homology arms, where a first end comprises a homology arm length of 0-9 nucleotides and a second end comprises a homology arm length of 50 nucleotides or more, as claimed in claims 1 and 14, would have been prima facie obvious over the prior art, for the reasons provided above. Therefore the intended result or functional property of homologous recombination occurring at one end of the donor DNA and non-homologous recombination occurring at the other end, as recited by claims 1 and 14, would have naturally flowed from the donor DNA construct of the prior art. Accordingly, for these reasons, the intended result or functional property recitation is not found to patentably distinguish the instantly claimed invention from the cited prior art.
Claim 14 further recites in the preamble “[a] method for producing a cell preparation for treating severe combined immunodeficiency;” however, the structure and manipulative actions of the method are the same as the “genome editing method” of claim 1.
If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. Shoes by Firebug LLC v. Stride Rite Children’s Grp., LLC, 962 F.3d 1362, 2020 USPQ2d 10701 (Fed. Cir. 2020) (The court found that the preamble in one patent’s claim is limiting but is not in a related patent); Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999). During examination, statements in the preamble reciting the purpose or intended use of the claimed invention must be evaluated to determine whether or not the recited purpose or intended use results in a structural difference (or, in the case of process claims, manipulative difference) between the claimed invention and the prior art. If so, the recitation serves to limit the claim. See, e.g., In re Otto, 312 F.2d 937, 938, 136 USPQ 458, 459 (CCPA 1963) (The claims were directed to a core member for hair curlers and a process of making a core member for hair curlers. The court held that the intended use of hair curling was of no significance to the structure and process of making.); In re Sinex, 309 F.2d 488, 492, 135 USPQ 302, 305 (CCPA 1962) (statement of intended use in an apparatus claim did not distinguish over the prior art apparatus). To satisfy an intended use limitation which is limiting, a prior art structure which is capable of performing the intended use as recited in the preamble meets the claim. See, e.g., In re Schreiber, 128 F.3d 1473, 1477, 44 USPQ2d 1429, 1431 (Fed. Cir. 1997) (anticipation rejection affirmed based on Board’s factual finding that the reference dispenser (a spout disclosed as useful for purposes such as dispensing oil from an oil can) would be capable of dispensing popcorn in the manner set forth in appellant’s claim 1 (a dispensing top for dispensing popcorn in a specified manner)) and cases cited therein. See MPEP 2111.02.
In this case, the structural features and manipulative actions recited in claim 14 would have been prima facie obvious over the prior art, for the reasons provided above. The preamble of claim 14 merely indicates an intended use of the genetically-modified cell for the treatment of severe combined immunodeficiency. Corn discloses that the genetically-modified cell is a lymphocyte (par. 289), and lymphocytes are a cell type used for treating severe combined immunodeficiency, as evidenced by Ferrari (pg. 226; fig. 2). Accordingly, Corn teaches editing a cell type suitable for treating severe combined immunodeficiency, as claimed. Therefore, the intended use recitation of the preamble is not found to result in a structural or manipulative difference that patentably distinguishes the instantly claimed invention from that of the cited prior art.
For these reasons, the methods according to claims 1, 3, 6, 14-15, 27-28 would have been prima facie obvious over the prior art.
Response to Declaration & Arguments
Applicant’s traversal filed on 10/01/2025 has been carefully considered but not found persuasive for the following reasons. As noted above, in view of the amendments to the claims, the previous rejection under 35 U.S.C. 102 has been withdrawn, and new grounds of rejection under 35 U.S.C. 103 have been provided. Therefore, applicant’s traversal has been addressed to the extent found relevant to the new grounds of rejection.
The declaration of Yutaka Hanazono under 37 C.F.R. 1.132, filed on 10/01/2025, is acknowledged. Hanazono is one of the inventors of the present application.
Hanazono declares that homologous recombination (HR) rarely occurs or at least is not the dominant recombination process in all cell types of adult human beings includes bone marrow stromal cells (MSCs), hematopoietic stem cells (HSCs), neural cells, myocardial cells, etc. (paragraph A). The inventors found a new recombination mechanism, termed “break induced concurrent Joining and Recombination (bicJR),” wherein non-homologous recombination (NHR) occurs at one end and HR at the other end (paragraphs B, D). The declarant reports observation of the bicJR mechanism in MSCs using a donor DNA construct having a 10 nt homology arm and 50 nt homology arm (paragraph C; see also Example 2 of the specification), in rat cortical neurons using a donor DNA construct having a 1,000 nt homology arm on one end and no homology arm on the other end (paragraph E; see also the previous declaration dated 11/14/2024), and in mouse embryonic stem (ES) cells and mouse common myeloid progenitor (CMP) cells using a donor DNA construct having a 1,000 nt homology arm on one end and no homology arm on the other end (paragraphs E-a to E-c).
Hanazono further declares that, although Example 1 of the specification did not detect the bicJR mechanism in hematopoietic stem cells (HSCs) with a donor DNA construct having a 10 nt homology arm and 50 nt homology arm, the occurrence of bicJR at a low rate that is not detectable cannot be ruled out due to technical limitations of the experiment (paragraphs F to G).
Hanazono further declares that the cited references (Basiri, Corn, Porteus and Ferrari) do not teach or fairly suggest the bicJR mechanism (paragraphs H to I-c). In contrast, the applicant has shown that bicJR takes place in various cell types, including surprisingly nerve cells where HR does not occur (paragraph J).
The declaration has been carefully considered but not found persuasive for the following reasons:
The occurrence of HR in cell types of adult human beings was not an unexpected result at the time of invention.
Yao et al. (2017) “Homology-mediated end joining-based targeted integration using CRISPR/Cas9” Cell research, 27(6), 801-814, discloses introducing into non-dividing neurons a donor DNA construct having 800 bp homology arms at each end via the homology-mediated end joining (HMEJ) mechanism. See, e.g., Abstract; Figures 1D, 2G, and 6C.
Nishiyama et al. (2017) “Virus-mediated genome editing via homology-directed repair in mitotic and postmitotic cells in mammalian brain” Neuron, 96(4), 755-768, discloses introducing into postmitotic neurons a donor DNA construct having left and right homology arms via the homology-directed repair (HDR) mechanism. See, e.g., Abstract; Figure 1.
Hu et al. (2017) “CRISPR/Cas9-mediated reversibly immortalized mouse bone marrow stromal stem cells (BMSCs) retain multipotent features of mesenchymal stem cells (MSCs)” Oncotarget, 8(67), 111847-111865, discloses introducing into bone marrow stromal stem cells (BMSCs) a donor DNA construct having 600-700 bp left and right homology arms via the homology-directed repair (HDR) mechanism. See, e.g., Abstract; Figure 1; pg. 111859.
Accordingly, the preponderance of evidence suggests that the occurrence of HR in cell types of adult human beings, including nerve cells, was not an unexpected result at the time of invention.
The features relied upon in the arguments are not recited by the present claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
In this case, the claims do not require that the edited cell is a non-dividing cell or nerve cell. Accordingly, the arguments are not commensurate with the scope of the present claims.
No evidence of criticality has been submitted regarding differences in the length of the homology arms between the present claims and the cited references
As outlined in the rejection under 35 U.S.C. 103, the only structural differences between the Corn disclosure and the instantly claimed invention are found in the homology arm lengths of the flanking regions of the donor DNA molecule. In particular, the instantly claimed invention recites a short end having a homology arm length of 0-9 nt; whereas, Corn teaches a short end having a homology arm length of 20-50 bp (claim 1) or 20-25 bp (par. 7). There is no evidence suggesting that increasing the homology arm length at the short end to 20 nt, as found in Corn, would not possess the claimed “bicJR” function, i.e., NHR on one end and HR on the other end.
Rather, applicant’s specification discloses that the short homology arm may have a length up to 50 nt (pg. 20, ll. 15, to pg. 21, ll. 5), suggesting that Corn’s donor DNA construct would possess the claimed function. "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). See also MPEP 2122. As outlined in the rejection, the claimed function is found to naturally flow from the structure taught by the cited references, absent evidence to the contrary.
A combinatorial outcome of NHR on one end and HR on the other end, coined by applicant as “break induced concurrent Joining and Recombination (bicJR),” appears to not depend on homology arm length but rather a natural property of the known HR pathways, as evidenced by He et al. (03 Jul 2018) “New turns for high efficiency knock-In of large DNA in human pluripotent stem cells”, Stem Cells International, Volume 2018, Article ID 9465028, 7 pages.
In describing the “Yao” disclosure (of record, full citation above), He discloses that “[i]t is likely that the high efficiency of HMEJ-based knock-in in studies by Yao et al. and Zhang et al. was achieved via the similar combinatory mechanisms [i.e., a combinatory outcome of both NHEJ-based knock-in and HDR-based knock-in].”
That is, the high efficiency of the HMEJ-based strategy in Yao was attributed to a combinatorial outcome of both NHEJ-based knock-in and HDR-based knock-in, which appears to be the same or at least similar to applicant’s “bicJR” mechanism, even though Yao used long, 800 bp left and right homology arms.
Accordingly, the preponderance of evidence suggests that the “bicJR” pathway is a natural combinatorial outcome regardless homology arm length.
For these reasons, the declaration is not found sufficiently persuasive to overcome the rejection of the present claims under 35 U.S.C. 103.
In addition to the above declaration, counsel’s remarks provided in the written response filed on 10/01/2025 have been carefully considered. The remarks reiterate the arguments presented in the declaration or otherwise rely thereon. Accordingly, the arguments are found to sufficiently addressed by the examiner’s response to the declaration and the new grounds of rejection under 35 U.S.C. 103 set forth above.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Applicant’s request for an interview is acknowledged. The interview request is granted. Applicant is invited to contact the examiner via telephone to schedule the interview at a time and date prior to submission of applicant’s next reply. Applicant may find the examiner’s contact information below.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES J GRABER whose telephone number is (571)270-3988. The examiner can normally be reached Monday-Thursday: 9:00 am - 4:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James D Schultz can be reached on (571)272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JAMES JOSEPH GRABER/Examiner, Art Unit 1631
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