DETAILED ACTION
Notice of Pre-AIA or AIA Status
Examiner prosecuting this application has changed.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s response filed 01/31/2026 has been received and considered entered. This is a response to amendments and arguments filed 01/31/2026.
Claims Status
Claims 1-26, 34-35 is/are cancelled. Claims 27-33, 36-53 is/are currently pending. Claims 27-33, 36-53 is/are under examination.
Information Disclosure Statement
The listing of references in the specification or arguments 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." See MPEP 609.05(c). Documents submitted as part of an applicant’s reply to an office action may be relied on by an applicant and may be considered; however, such documents must be submitted. Applicant has referenced publications which have not been provided or made of record. Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claims 27-33 and 36-53 contain amendments which are not in black text and as a result, appear in low resolution compared to the surrounding text. For legibility, it is requested that underlining, striking through, and bracketing of claim amendments be made in black instead of gray or a different color.
Claim Rejections - 35 USC § 112
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.
Claims 27-33, 36-42, 44-53 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.
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”).
Claim 27 recites a guide RNA comprising “at least one internal non-nucleotide linker”. Claim 43 recites specific non-nucleotide linker structures, encompassing a subset of non-nucleotide linkers described by the present disclosure. The disclosure provides a limited number of additional non-nucleotide linkers (see pages 22-27). These non-nucleotide linker structures are not representative of the entire genus of “non-nucleotide linkers” (see, for example, Reynolds, 1996, which teaches non-nucleotide linkers inserted into RNA sequences which differ significantly in chemical structure from the linkers of the instant disclosure).
Claims 50 and 52-53 recite the limitations that the linker comprises at least one amide bond, thioether bond, or triazole in its structure, respectively. While the described linkers each comprise at least one of these structures, they are not representative of the full genus of non-nucleotide linkers comprising at least one amide bond, thioether bond, or triazole (see Reynolds, which teaches multiple non-nucleotide linkers comprising amide bonds and which are not represented by the disclosed species of non-nucleotide linkers). Claims 50 and 52-53 are thus not sufficiently described such that an artisan could determine that the applicants were in possession of the entire genus of non-nucleotide linkers comprising at least one amide bond, thioether bond, or triazole.
As the present disclosure only provides a written description of a limited number of species of non-nucleotide linkers which are not representative of the entire genus of non-nucleotide linkers which can be inserted into an RNA sequence, an artisan would not be able to determine that the applicants were in possession of the entire genus of non-nucleotide linkers. As claims 28-33, 36-42, 44-46, and 50-53 read on the entire genus of non-nucleotide linkers recited in claim 27, claims 28-33, 36-42, 44-46, and 50-53 also lack sufficient written description.
Claims 27-33, 36-42, 44, and 47-53 claim “guide RNA [comprising] at least one internal non-nucleotide linker” (see claim 27). The genus of gRNAs created by this phrasing encompasses at least one non-nucleotide linker positioned anywhere within the gRNA, including within a crRNA, within a tracrRNA, and between a crRNA and a tracrRNA. However, the disclosure only describes gRNAs wherein the non-nucleotide linker is positioned between a crRNA and a tracrRNA, or positioned within a tracrRNA (paragraphs [0014], [0022]-[0023], [0079]-[0081] and Figs. 1 and 4 depict the former; paragraphs [0012], [0080]-[0081] and Figs. 1 and 4 depict the latter). As the insertion of a non-nucleotide linker within a crRNA would alter the structural characteristics of the crRNA and possibly eliminate the capacity of the crRNA to target a target sequence (eliminating the function of the RNA molecule as a guide RNA), descriptions of non-nucleotide linkers positioned within a tracrRNA or between a tracrRNA and a crRNA are not considered representative of insertion of a non-nucleotide linker within a crRNA. Claims 28-33, 36-44, and 47-53 depend on claim 27 but do not sufficiently further describe the full scope of the claimed guide RNA.
Claim 44 recites that the non-nucleotide linker is “positioned between either two bases. The disclosure does not describe any non-nucleotide linkers positioned between two bases.
Claim 51 recites that the non-nucleotide linker “comprises at least one OCH2CH2O in its structure”. However, only one species of non-nucleotide linkers comprising an OCH2CH2O are described (see “SM(PEG)2 on page 27). This is not representative of the full scope of the genus of all non-nucleotide linkers comprising an OCH2CH2O in their structures.
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.")."
Claims 27-33, 36-42, 44-53 are rejected for failing to comply with the written description requirement, as the disclosure does not show that the applicants were in possession of the full scope of the claimed genus of non-nucleotide linkers or the full scope of the claimed genus of positioning of internal non-nucleotide linkers within gRNA molecules.
Response to Arguments
Applicant's arguments filed 01/31/2026 have been fully considered but they are not persuasive. Applicant argues that the specification teaches multiple structures of non-nucleotide linkers, lgRNA preparation protocols and reagents, and positionings of non-nucleotide linkers within a gRNA (e.g., in an exposed tetraloop) (page 12 of arguments). Applicant argues that “a significantly large number of distinct non-nucleotide linkers can be made based on Applicant’s teaching by a person of ordinary skills in the art” (page 12). However, a large number of species does not necessarily describe or is representative of the entire scope of a broad genus—in this case, the genus of guide RNAs comprising non-nucleotide linkers. For example, the instant disclosure does not suggest or teach species representative of some of the non-nucleotide linkers within gRNAs described by US20160102322A1 (Ravinder), which are encompassed by the broad genus of guide RNAs comprising non-nucleotide linkers.
Applicant argues that “the Examiner asserts a non-nucleotide linker cannot be in the crRNA segment, which is not true” (page 13). On page 9 of the non-final rejection mailed 10/31/2025, the Examiner argued that a non-nucleotide linker within a crRNA would alter the structural characteristics of the crRNA and possibly eliminate functional attributes of the crRNA, and that the applicant did not disclose such a functional crRNA comprising an internal non-nucleotide linker and thus had not described non-nucleotide linkers positioned within a crRNA. Applicant references US2025263693A1 to show that crRNA comprising internal non-nucleotide linkers are enabled. However, the instant disclosure does not provide any description of crRNA comprising internal non-nucleotide linkers, and an artisan at the time of filing would not have been able to assume that a crRNA comprising any internal non-nucleotide linker anywhere within the crRNA would be a functional crRNA based on descriptions of tracrRNA with internal non-nucleotide linkers or crRNA linked to tracrRNA by non-nucleotide linkers. Therefore, an artisan at the time of filing would not have been able to determine that the applicant was in possession of crRNA comprising internal non-nucleotide linkers.
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) 27, 37-42, 45-47, 50, 52-53 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Ravinder (US20160102322, of record, claiming priority to US 63061961, filed 10/09/2014). This rejection is amended as necessitated by claim amendments, and is maintained.
Regarding claim 27, Ravinder teaches a method of preparing a cell comprising at least one guide RNA, wherein the guide RNA comprises at least one internal non-nucleotide linker (paragraphs [0151]-[0158]; Table 6; claims 19-20, 25).
Regarding claim 37, Ravinder teaches that the cell further comprises a Cas protein (claims 19, 21).
Regarding claim 38, Ravinder teaches that the Cas9 protein complexes the guide RNA in the cell (paragraph [0038]).
Regarding claim 39, Ravinder teaches that the Cas9 protein may be a fusion protein (which is considered to be a “Cas protein-peptide conjugate”) (paragraph [0018]).
Regarding claim 40, Ravinder teaches that the Cas9 protein complexes the guide RNA in the cell (paragraph [0038]). Ravinder teaches that the Cas9 protein can be a fusion protein (paragraph [0018]).
Regarding claims 41-42, Ravinder teaches that the Cas/gRNA complexes can be transfected using delivery lipids or cell-penetrating peptides, thereby anticipating a cell comprising the delivery lipids or cell-penetrating peptides (paragraphs [0206], [0270]).
Regarding claims 45-46, Ravinder teaches that the internal non-nucleotide linker is positioned between a crRNA and a tracrRNA, or between a first fragment of a tracrRNA and a second fragment of the tracrRNA (paragraphs [0151], [0158]; Fig. 11).
Regarding claims 47-49, Ravinder teaches that the internal non-nucleotide linker can comprise 4-60 covalently-bonded atoms (see Table 6, products of, “Thiol-ene”, “Isocyanates”, “Epoxy or aziridine”, “Oxanorbornadiene cycloaddition”, “Aldehyde-aminooxy”, “Quadricyclane ligation”).
Regarding claim 50, Ravinder teaches an internal non-nucleotide linker that comprises at least one amide bond (Table 6, see product of “Isocyanates” reaction).
Regarding claim 52, Ravinder teaches an internal non-nucleotide linker that comprises at least one thioether bond (Table 6, see products of “Thiol-yne” reaction, “Epoxy or aziridine” reaction, and “Quadri-cyclane ligation”).
Regarding claim 53, Ravinder teaches an internal non-nucleotide linker that comprises at least one triazole (Table 6, see products of “Norbornene cycloaddition with azide”, “Oxanorbornadiene cycloaddition”).
Response to Arguments
Applicant's arguments filed 01/31/2026 have been fully considered but they are not persuasive.
Applicant argues that “Ravinder still does not teach or suggest any non-nucleotide linkers of a guide RNA” (page 15), and disagrees that the disclosure of Brown, incorporated by reference by Ravinder and which teaches non-nucleotide linkers in RNA molecules, would provide sufficient enablement for an artisan to know how to insert the non-nucleotide linkers of Ravinder into the gRNA of Ravinder. Applicant argues that the disclosure of Brown would not be enabling because “Ravinder does not teach or suggest any chemical structures of Brown to be used in a guide RNA” and because “the technique of Brown was not applied to a guide RNA” (page 15).
In paragraph [0151], Ravinder teaches that:
“Another method that may be used to connect RNA segments is by ‘click chemistry’ (see, e.g., U.S. Pat. Nos. 7,375,234 and 7,070,941, and US Patent Publication No. 2013/0046084, the entire disclosures of which are incorporated herein by reference). For example, one click chemistry reaction is between an alkyne group and an azide group (see FIG. 11). Any click reaction can be used to link RNA segments (e.g., Cu-azide-alkyne, strain-promoted-azide-alkyne, Staudinger ligation, tetrazine ligation, photo-induced tetrazole-alkene, thiol-ene, NHS esters, epoxides, isocyanates, and aldehyde-aminooxy). Ligation of RNA molecules using a click chemistry reaction is advantageous because click chemistry reactions are fast, modular, efficient, often do not produce toxic waste products, can be done with water as a solvent, and can be set up to be stereospecific.”
Ravinder then teaches in paragraphs [0155]-[0158] that the explicit purpose of such (and other) methods of ligating RNA in the context of the invention of Ravinder is to ligate segments of a guide RNA. Figure 11 of Ravinder explicitly shows a triazole linker linking two segments of a guide RNA.
It is noted that only claim 43 (not rejected under 35 USC 102 above) requires that the linkers be covalently bound to specific atoms of nucleotides, and as such, the teachings of Brown, regarding the specific atoms of a nucleotide covalently bound to a linker, are not required for the teachings of Ravinder to anticipate the claims rejected above. Brown was merely introduced in the response to Applicant’s arguments to show that Ravinder referenced publications that enabled the guide RNAs comprising non-nucleotide linkers taught by Ravinder.
A guide RNA is still an RNA molecule. The disclosure of Brown is enabling of non-nucleotide linkers in any RNA molecule. Ravinder explicitly teaches in paragraph [0151] that the guide RNAs of Ravinder can comprise internal non-nucleotide linkers introduced through click-chemistry techniques such as those taught by Brown as usable in a generic RNA molecule, and Fig. 11 of Ravinder shows a guide RNA comprising a non-nucleotide linker formed through click chemistry (“Click Connector 1 (e.g., propargyl) on 3’ Terminus; crRNA/variable segment”, “Click Connector 2 (e.g., azide) on 5’ Terminus; tracrRNA/Constant Segment”, “Click Connected guide RNA (e.g., via triazole)”).
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It would be obvious to an artisan that Brown enables methods of ligating any RNA nucleotides through propargyl-azide click chemistry, forming a triazole linker, including the guide RNA of Ravinder Fig. 11.
Applicant further argues that because one reaction of Ravinder Table 6 is shown to be incorrect (see pages 15-16 of arguments, regarding the NHS ester reaction), “the Ravinder reference does not provide a reliable or enabling roadmap for applying such reactions to synthesize a functional guide RNA incorporating a non-nucleotide linker” (page 16). However, multiple references found in the prior art teach that other reactions of Table 6 are correct. The Thiol-yne click reaction is taught by Yao (2013) and Lowe (2014) (Figure below from Lowe).
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The Thiol-ene reaction is taught by Lowe (2010) (see below).
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The Isocyanate reaction is taught by Arnold (1956) (see below).
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The “Epoxy or aziridine” reaction is taught by De (2012) (see below).
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The aldehyde-aminooxy reaction is taught by Mueller (2011) (see below, from page 4).
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The copper-catalyzed azid-alkyne reaction is taught by Liang (2011) (see below).
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The strain-promoted azid-alkyne cycloaddition, tetrazine ligation, and photo-induced tetrazole-alkene reactions are taught by Jewett (2010) (see below).
Fig. 2:
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Scheme 2:
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Scheme 3:
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Scheme 4:
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Stockmann (2011) teaches the [4+1] cycloaddition reaction (see below).
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The Staudinger ligation is taught by Kohn (2004) (shown below; Ravinder Table 6 omits the oxygen double bonded to the PPh2, but is otherwise correct).
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The quadricyclane ligation reaction is taught by Sletten (2011) (see below).
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Thus, while the NHS ester and Staudinger ligation reactions shown in Ravinder Table 6 are not consistent with the reactions as they are known in the art, the remainder of the reactions in Table 6 are consistent with the prior art, and an artisan familiar with these chemical reactions would recognize that they are correctly depicted in Table 6.
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.
Claim(s) 27-30 and 33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ravinder (US20160102322A1), in view of Bhatia (WO2015089465A1). This rejection is amended as necessitated by claim amendments and maintained.
Regarding claim 27, Ravinder teaches a method of preparing a cell comprising at least one guide RNA, wherein the guide RNA comprises at least one internal non-nucleotide linker (paragraphs [0151]-[0158]; Table 6; claims 19-20, 25).
However, Ravinder does not teach that the guide RNA comprises a spacer targeting a pathogenic gene or viral DNA.
Bhatia teaches a CRISPR system comprising a guide RNA comprising a spacer targeting a pathogenic gene or viral DNA.
Regarding claims 28-29, Bhatia teaches a CRISPR-Cas system which comprises a gRNA comprising a spacer sequence targeting a pathogenic viral gene (a viral gene which has integrated into the host genome) (paragraph [0425]).
Regarding claim 30, Bhatia teaches that the spacer targets an HBV gene (paragraphs [0425], [0432]-[0433]).
Regarding claim 33, Bhatia teaches a sequence 100% identical to instant SEQ ID NO:38 (sixth sequence listed on page 164, see alignment below).
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It would have been obvious to one of ordinary skill in the art prior to the effective filing date to have used a guide RNA comprising a non-nucleotide linker as taught by Ravinder in the invention of Bhatia. Doing so would have been no more than employing the technology for its intended use, i.e. making guide RNAs for editing target sequences. Delivery of the gRNAs to cells would result in the instantly claimed cells including a cell comprising a guide RNA with an internal non-nucleotide linker and the spacer sequence comprising instant SEQ ID NO:38. Moreover, as taught by Ravinder, the ligation of RNA molecules using click chemistry to create guide RNA comprising internal non-nucleotide linkers “is advantageous because click chemistry reactions are fast, modular, efficient, often do not produce toxic waste products, can be done with water as a solvent, and can be set up to be stereospecific” (paragraph [0151]), providing a material benefit to using the non-nucleotide linkers and gRNA structures of Ravinder in the invention of Bhatia.
Claim(s) 27-29, 31, 33, 36 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ravinder (US2016102322), in view of Khalili (US20160017301, of record). This rejection is amended as necessitated by claim amendments and maintained.
Regarding claim 27, Ravinder teaches a method of preparing a cell comprising at least one guide RNA, wherein the guide RNA comprises at least one internal non-nucleotide linker (paragraphs [0151]-[0158]; Table 6; claims 19-20, 25).
However, Ravinder does not teach that the guide RNA comprises a spacer targeting a pathogenic gene or viral DNA.
Khalili teaches a CRISPR system comprising a guide RNA comprising a spacer targeting a pathogenic gene or viral DNA.
Regarding claims 28-29 and 31, Khalili teaches a CRISPR system comprising at least one guide RNA comprising a spacer sequence targeting a pathogenic viral HIV gene (claims 1-7, 12; Abstract; paragraphs [0006], [0051]: the spacer sequence may target an LTR sequence or a viral protein-coding sequence).
Regarding claim 33, Khalili teaches that the spacer sequence is complementary to SEQ ID NOs:87, 96, 110, or 121, identical to instant SEQ ID NOs:47-50, respectively. These target sequences are within double-stranded proviral HIV DNA (claims 4-7, 17-20). As such, a spacer targeting a sequence complementary to SEQ ID NOs:87, 96, 110, or 121 would target the complexed CRISPR nuclease also to the sequence identical to SEQ IDNOs:87, 96, 110, or 121, as these two sequences (complementary and identical) are paired in the dsDNA molecule. As the spacers of Khalili target the same double stranded sequence in the target proviral genome as the claimed spacers of SEQ ID NOs:47-50, Khalili obviates instant spacer sequences of SEQ ID NOs:47-50. (instant SEQ ID NO:47 aligned to SEQ ID NO:87 below).
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Regarding claim 36, Khalili teaches that the CRISPR system may also be administered with another anti-viral therapeutic agent, such as anti-retroviral agents, including reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, integrase inhibitors, and multi-class combination agents (paragraph [0102]).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date to have used a guide RNA comprising a non-nucleotide linker as taught by Ravinder in the invention of Khalili. Doing so would have been no more than employing the technology for its intended use, i.e. making guide RNAs for editing target sequences. Delivery of the gRNAs to cells would result in the instantly claimed cells including a cell comprising a guide RNA with an internal non-nucleotide linker and the spacer sequence comprising instant SEQ ID NO:47-50 or sequences complementary to SEQ ID NOs:47-50. Moreover, as taught by Ravinder, the ligation of RNA molecules using click chemistry to create guide RNA comprising internal non-nucleotide linkers “is advantageous because click chemistry reactions are fast, modular, efficient, often do not produce toxic waste products, can be done with water as a solvent, and can be set up to be stereospecific” (paragraph [0151]), providing a material benefit to using the non-nucleotide linkers and gRNA structures of Ravinder in the invention of Khalili.
Claim(s) 27-29, 32-33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ravinder (US2016102322A1), in view of Quake (WO2015184259A1: EFD 05/30/2014; of record). This rejection is amended as necessitated by claim amendments and maintained.
Regarding claim 27, Ravinder teaches a method of preparing a cell comprising at least one guide RNA, wherein the guide RNA comprises at least one internal non-nucleotide linker (paragraphs [0151]-[0158]; Table 6; claims 19-20, 25).
However, Ravinder does not teach that the guide RNA comprises a spacer targeting a pathogenic gene or viral DNA.
Quake teaches a CRISPR system comprising a guide RNA comprising a spacer targeting a pathogenic gene or viral DNA.
Regarding claims 28-29 and 32, Quake teaches a CRISPR system comprising a guide RNA, wherein the guide RNA comprises a spacer sequence targeting a pathogenic herpesvirus gene (claims 1, 3-5, 7-8; pages 1-2; Table S-1 page 29; pages 14-15).
Regarding claim 33, Quake teaches gRNA spacer sequences of SEQ ID NO:1, which is comprised within instant SEQ ID NO:51 (see alignment below).
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As SEQ ID NO:1 comprises the first 20 of 23 nucleotides of instant SEQ ID NO:51, it would have been obvious to an artisan at the time of filing that Quake teaches guide RNAs targeting the same sequence within the EBV herpesvirus genome as instant SEQ ID NO:51 (see alignment below between instant SEQ ID NO:51 and EBV strain B95-8 genome).
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The only difference between these two sequences is that the instant SEQ ID NO:51 comprises three additional bases. It would have been obvious to an artisan at the time of filing that the lengthening of the spacer sequence by three nucleotides compared to the spacer sequence of Quake would be an obvious variant and would not alter the activity of the CRISPR system comprising the spacer sequence.
It would have been obvious to one of ordinary skill in the art prior to the effective filing date to have used a guide RNA comprising a non-nucleotide linker as taught by Ravinder in the invention of Quake. Doing so would have been no more than employing the technology for its intended use, i.e. making guide RNAs for editing target sequences. Delivery of the gRNAs to cells would result in the instantly claimed cells including a cell comprising a guide RNA with an internal non-nucleotide linker and the spacer sequence comprising instant SEQ ID NO:51. Moreover, as taught by Ravinder, the ligation of RNA molecules using click chemistry to create guide RNA comprising internal non-nucleotide linkers “is advantageous because click chemistry reactions are fast, modular, efficient, often do not produce toxic waste products, can be done with water as a solvent, and can be set up to be stereospecific” (paragraph [0151]), providing a material benefit to using the non-nucleotide linkers and gRNA structures of Ravinder in the invention of Quake.
Claim(s) 27, 43-44, 47 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ravinder (US2016102322A1), in view of Brown (US20130046084A1). This rejection is amended as necessitated by claim amendments and maintained.
Regarding claim 27, Ravinder teaches a method of preparing a cell comprising at least one guide RNA, wherein the guide RNA comprises at least one internal non-nucleotide linker (paragraphs [0151]-[0158]; Table 6; claims 19-20, 25).
However, Ravinder does not teach which atoms of the 3’- and 5’-terminal nucleotides of the RNA segments are covalently bound to the non-nucleotide linker.
Brown teaches non-nucleotide linkers for ligating oligonucleotides.
Regarding claim 43, Brown teaches triazole phosphodiester mimics linking two nucleotides in a method of ligating one or more oligonucleotides (claim 1). Brown teaches the following non-nucleotide linker (triazole phosphodiester mimic) linking the sugar of one nucleotide to the sugar of a second nucleotide (claim 1):
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This non-nucleotide linker and the specific atoms of each nucleotide covalently bound to the linker are identical to linker nNt-i, except that the linker shown in Brown claim 1 links DNA nucleotides, while the linker nNt-i is depicted in instant claim 43 linking RNA molecules. Brown teaches that the claimed linkers can be used to link RNA nucleotides using equivalent reactions (paragraph [0012]). Thus, Brown renders obvious claimed linker nNt-i.
Regarding claim 44, Brown teaches non-nucleotide linkers covalently bound to the sugar of a first RNA nucleotide and the sugar of a second RNA nucleotide (claim 1; paragraph [0012]).
Regarding claim 47, Brown teaches non-nucleotide linkers comprising a chain of 4-7 covalently-bound atoms (claim 1).
Ravinder teaches that a “method that may be used to connect RNA segments is by ‘click chemistry’ (see, e.g., … US Patent Publication No. 2013/0046084, the entire disclosures of which are incorporated herein by reference)”. Brown (US2013/0046084) teaches non-nucleotide linkers for ligating DNA or RNA sequences and specific atoms of a first oligonucleotide segment, a second oligonucleotide segment, and non-nucleotide linker which are covalently bonded to one another. The linkers taught by Brown, including the atoms of nucleotides bound to the linkers, include claimed non-nucleotide linker nNt-i. As Ravinder teaches that the linkers of Brown were applicable in the invention of Ravinder as structures for linking segments of a guide RNA, it would have been obvious to an artisan at the time of filing to use the non-nucleotide linkers of Brown to ligate the guide RNA segments of Ravinder for use in the methods of Ravinder.
Claim(s) 27 and 51 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ravinder (US2016102322A1), in view of Zlatev (US20120220761A1). This rejection is amended as necessitated by claim amendments and maintained.
Regarding claim 27, Ravinder teaches a method of preparing a cell comprising at least one guide RNA, wherein the guide RNA comprises at least one internal non-nucleotide linker (paragraphs [0151]-[0158]; Table 6; claims 19-20, 25).
However, Ravinder does not teach non-nucleotide linkers which comprise at least one OCH2CH2O.
Zlatev teaches that RNA molecules can be ligated using polyethylene glycols.
Regarding claim 51, Zlatev teaches that a first RNA strand and a second RNA strand can be connected by a polyethylene glycol linker or a hexaethylene glycol linker (paragraph [0097]) joining the sugars of a nucleotide of the first RNA strand and of a nucleotide of the second RNA strand (paragraphs [0101]-[0103]). Hexaethylene glycol linker has the following structure:
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Hexaethylene glycol is a species of polyethylene glycol comprising 6 repeats of the ethylene glycol monomer, and comprises, as shown above, multiple OCH2CH2O structures. Hexaethylene glycol comprises a chain of 42 covalently bonded atoms. As Zlatev teaches that polyethylene glycol, generally, can be used as a non-nucleotide linker, an artisan would interpret that shorter polyethylene glycol linkers than hexaethylene glycol were obvious and encompassed by the teachings of Zlatev. Such encompassed PEG linkers would include pentaethylene glycol (5 repeats of the ethylene glycol monomer; a chain of 35 covalently bonded atoms).
Both Ravinder and Zlatev teach that RNA nucleotides can be linked using non-nucleotide linkers. Zlatev teaches that such linkers can include polyethylene glycol linkers, including hexaethylene glycol, for the purpose of inhibiting separation of the linked strands in a cell (paragraph [0097]). The linkers taught by Ravinder were chosen for the same purpose and because they are synthesized using “click chemistry”, and because Ravinder teaches that “click chemistry” is useful because “click chemistry” “is advantageous because click chemistry reactions are fast, modular, efficient, often do not produce toxic waste products, can be done with water as a solvent, and can be set up to be stereospecific” (paragraph [0151]). It would have been obvious to a person of ordinary skill in the art at the time of filing that the non-nucleotides linkers of Zlatev and Ravinder were interchangeable; their different structures were not taught to have an effect on the functionality or activity of the bonded RNA molecules and were taught to effectively link RNA molecules. As such, it would have been obvious to an artisan at the time of filing to use the non-nucleotide linkers of Zlatev in the CRISPR system and methods of Ravinder instead of the click-chemistry linkers of Ravinder.
Response to Arguments
Applicant's arguments filed 01/31/2026 have been fully considered but they are not persuasive.
The alleged deficiencies of Ravinder and Brown are addressed in the response to arguments regarding the rejection of claims over 35 USC 102, above.
On pages 21-22, Applicant further argues that “Designing a functional non-nucleotide linker requires specific structural modifications to guide RNA segments, which Ravinder does not provide. The secondary references do not address this gap, as they are silent on non-nucleotide linkers of a guide RNA.” As addressed above, the invention of Ravinder is drawn to guide RNAs, and Ravinder teaches multiple different non-nucleotide linkers within a guide RNA, including a graphical depiction in Figure 11. The disclosure of Brown is enabling of non-nucleotide linkers in any RNA, and as a guide RNA is an RNA molecule, and Ravinder teaches where in the guide RNA the linker may be positioned, and Ravinder explicitly references the disclosure of Brown as enabling techniques for click-chemistry ligation of RNA molecules, an artisan would understand that the RNA ligation techniques of Brown could be applied to the guide RNA of Ravinder.
Applicant draws attention to Applicant’s patent US 10059940 B2 (page 22). Pending claim 21 is so broad as to encompass any non-nucleotide linker in a guide RNA, while the independent claim of the issued patent is significantly narrower in scope. Furthermore, the Nature Biotechnology review paper referenced in the arguments cites this issued patent in “Recent patents in siRNA, antisense oligonucleotides, and CRISPR”; it does not teach that this patent was the first to describe gRNAs comprising non-nucleotide linkers. See “RNA-Based Therapies” (2019), provided herein by the Examiner. Applicant further cites Brown (2019), but has not provided a copy and did not provide sufficient information such that the Examiner could find Brown (2019). Even if either reference had taught that the ~940 patent was the first to describe gRNAs comprising non-nucleotide linkers, such an assertion cannot be assumed to be accurate without any further search of the art. Indeed, as described in the rejections above, gRNAs comprising internal non-nucleotide linkers had been described in the art prior to the filing of the instant application.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
US10059940B2:
Claims 27-33, 36-50, 52-53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-25 of U.S. Patent No. 10059940. Although the claims at issue are not identical, they are not patentably distinct from each other.
~940 claimed an lgRNA for use as one component of a CRISPR-associated protein complex, wherein the lgRNA had the structure described in instant claim 27 (~940 claim 1). The lgRNA may comprise a spacer sequence targeted to an HBV, HIV, or EBV genome sequence (claims 6-9; claim 7 encompasses spacers of SEQ ID NOs:36-46, identical to instant SEQ ID NOs:36-46). ~940 claims the lgRNAs for delivery to animal or human cells (claim 13), obviating cells comprising the lgRNAs and generic methods of preparing such cells, with no recited method steps. With regard to claim 33, the portion of the specification supporting claims 23-25 indicates that spacers directed against HIV and HSV include SEQ ID NOs:47-57, identical to instant SEQ ID NOs:47-57. Regarding instant claims 36-37, 41-42, the lgRNA may be formulated together with direct acting antiviral agents (claims 18-21), a Cas9 protein (claim 16) (which may be engineered, claim 17), cell-penetrating peptides (claim 14), and cationic lipids (claim 13). Regarding instant claims 39-40, the portion of the specification supporting the Cas9 protein indicates that “Cas9” includes Cas9-peptide fusions (col. 57 line 59-col.58 line 47). Absent evidence to the contrary, presence of both the lgRNA and Cas9 conjugate in the same composition leads to the formation of the complex of instant claim 40. Regarding instant claims 43-44, 47-50 and 52-53, ~940 claims non-nucleotide linkers nNt-i, nNt-ii, nNt-iii, nNt-iv, nNt-v, nNt-ix, and nNt-x (claim 2), wherein the linker is positioned between two sugars of two nucleotides. Regarding instant claims 45-46, ~940 claims non-nucleotide linkers positioned between a crRNA and a tracrRNA and between a first segment and a second segment of a tracrRNA (claim 3).
Claim 48-49 and 51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 13 of U.S. Patent No. 10059940, as applied to instant claim 27 above, in view of Zlatev (US20120220761A1).
~940 recites or obviates all the required limitations of instant claim 27, as described above. However, ~940 does not claim a non-nucleotide linker comprising the structure OCH2CH2O.
Zlatev teaches that RNA molecules can be ligated using polyethylene glycols.
Regarding claims 48-49 and 51, Zlatev teaches that a first RNA strand and a second RNA strand can be connected by a polyethylene glycol linker or a hexaethylene glycol linker (paragraph [0097]) joining the sugars of a nucleotide of the first RNA strand and of a nucleotide of the second RNA strand (paragraphs [0101]-[0103]). Hexaethylene glycol linker has the following structure:
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Hexaethylene glycol is a species of polyethylene glycol comprising 6 repeats of the ethylene glycol monomer, and comprises, as shown above, multiple OCH2CH2O structures (required by claim 51). Hexaethylene glycol comprises a chain of 42 covalently bonded atoms (required by claim 49). As Zlatev teaches that polyethylene glycol, generally, can be used as a non-nucleotide linker, an artisan would interpret that shorter polyethylene glycol linkers than hexaethylene glycol were obvious and encompassed by the teachings of Zlatev. Such encompassed PEG linkers would include pentaethylene glycol (5 repeats of the ethylene glycol monomer; a chain of 35 covalently bonded atoms) (required by claim 48).
Both ~940 and Zlatev teach that RNA nucleotides can be linked using non-nucleotide linkers. Zlatev teaches that such linkers can include polyethylene glycol linkers, including hexaethylene glycol, for the purpose of inhibiting separation of the linked strands in a cell (paragraph [0097]). It would have been obvious to a person of ordinary skill in the art at the time of filing that the non-nucleotides linkers of Zlatev and ~940 were interchangeable; their different structures were not taught to have an effect on the functionality or activity of the bonded RNA molecules and were taught to effectively link RNA molecules. As such, it would have been obvious to an artisan to use the non-nucleotide linkers of Zlatev in the CRISPR system of ~940 instead of the linkers of ~940.
US11667914B2:
Claims 26-29, 32-33, 36-42 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5-22 of U.S. Patent No. 11667914. Although the claims at issue are not identical, they are not patentably distinct from each other.
~914 claims a method of cleaving a herpesvirus linear DNA, episomal DNA, and DNA chromosomally integrated into the genome of a host cell, including the steps of: a) treating the host cell infected with herpesviruses with a composition comprising a CRISPR-associated endonuclease, and at least one lgRNA having a spacer sequence that is complementary to a target sequence in a herpesvirus genome; and b) cleaving said herpesvirus linear DNA, episomal DNA, and integrated DNA< wherein said lgRNA comprises one or more internal non-nucleotide linkers (claim 1). It would be obvious to an artisan that such a method would result in cells comprising the lgRNAs. The gRNA may target the RS1, UL30, RL1, or UL5 genes of HSV-1 or -2 (claims 7-10). The spacers may comprise one of SEQ ID NOs:51-57 (identical to instant SEQ ID NOs:51-57) (claim 2). The lgRNAs may be formulated with direct-acting antiviral agents (claims 17-18), Cas9 (claim 16) (which may be engineered, claim 17), cationic lipids (claim 12), and cell-penetrating peptides (claim 13). Regarding instant claims 39-40, the portion of the specification supporting the Cas9 protein indicates that “engineered Cas9” includes Cas9-peptide fusions (col. 59, lines 46-57).
Claim 45-47, 50, 52-53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 13 of U.S. Patent No. 11667914, as applied to instant claim 27 above, in view of Ravinder (US2016102322).
~914 recites all the required limitations of instant claim 27, as described above. However, ~914, while claiming non-nucleotide linkers, does not claim non-nucleotide linker structures.
Regarding claims 45-46, Ravinder teaches that the internal non-nucleotide linker is positioned between a crRNA and a tracrRNA, or between a first fragment of a tracrRNA and a second fragment of the tracrRNA (paragraphs [0151], [0158]; Fig. 11).
Regarding claim 47, Ravinder teaches that the internal non-nucleotide linker can comprise a chain of 4-9 covalently-bonded atoms (see Table 6, products of “NHS esters”, “Thiol-ene”, “Isocyanates”, “Epoxy or aziridine”, “Oxanorbornadiene cycloaddition”, “Staudinger ligation”, and “Aldehyde-aminooxy”).
Regarding claim 50, Ravinder teaches an internal non-nucleotide linker that comprises at least one amide bond (Table 6, see product of “Isocyanates” reaction).
Regarding claim 52, Ravinder teaches an internal non-nucleotide linker that comprises at least one thioether bond (Table 6, see products of “Thiol-yne” reaction, “Epoxy or aziridine” reaction, and “Quadri-cyclane ligation”).
Regarding claim 53, Ravinder teaches an internal non-nucleotide linker that comprises at least one triazole (Table 6, see products of “Norbornene cycloaddition with azide”, “Oxanorbornadiene cycloaddition”).
Ravinder teaches non-nucleotide linkers for ligating RNA segments to form a guide RNA, as claimed by the instant claims and generally by the claims of ~914. As Ravinder teaches that these linker structures are applicable to ligating RNA molecules to form a guide RNA, it would have been obvious to an artisan at the time of filing to use the non-nucleotide linkers of Ravinder to ligate the guide RNA segments of ~914 for use in the CRISPR system of ~914.
Claim 43-44, 47, 53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 13 of U.S. Patent No. 11667914, as applied to instant claim 27 above, in view of Brown (US20130046084A1).
~914 recites all the required limitations of instant claim 27, as described above. However, ~914, while claiming non-nucleotide linkers, does not claim non-nucleotide linker structures.
Brown teaches non-nucleotide linkers for ligating oligonucleotides.
Regarding claims 43 and 53, Brown teaches triazole phosphodiester mimics linking two nucleotides in a method of ligating one or more oligonucleotides (claim 1). Brown teaches the following non-nucleotide linker (triazole phosphodiester mimic) linking the sugar of one nucleotide to the sugar of a second nucleotide (claim 1):
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This non-nucleotide linker and the specific atoms of each nucleotide covalently bound to the linker are identical to linker nNt-i, except that the linker shown in Brown claim 1 links DNA nucleotides, while the linker nNt-i is depicted in instant claim 43 linking RNA molecules. Brown teaches that the claimed linkers can be used to link RNA nucleotides using equivalent reactions (paragraph [0012]). Thus, Brown renders obvious claimed linker nNt-i.
Regarding claim 44, Brown teaches non-nucleotide linkers covalently bound to the sugar of a first RNA nucleotide and the sugar of a second RNA nucleotide (claim 1; paragraph [0012]).
Regarding claim 47, Brown teaches non-nucleotide linkers comprising a chain of 4-7 covalently-bound atoms (claim 1).
Brown teaches non-nucleotide linkers for ligating DNA or RNA sequences and specific atoms of a first oligonucleotide segment, a second oligonucleotide segment, and non-nucleotide linker which are covalently bonded to one another. The linkers taught by Brown, including the atoms of nucleotides bound to the linkers, include claimed non-nucleotide linker nNt-i. As Brown teaches that these linker structures are applicable to ligating RNA molecules, it would have been obvious to an artisan at the time of filing to use the non-nucleotide linkers of Brown to ligate the guide RNA segments of ~914 for use in the CRISPR system of ~914.
Claim 48-49 and 51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 13 of U.S. Patent No. 11667914, as applied to instant claim 27 above, in view of Zlatev (US20120220761A1).
~914 recites all the required limitations of instant claim 27, as described above. However, ~914, while claiming non-nucleotide linkers, does not claim non-nucleotide linker structures.
Zlatev teaches that RNA molecules can be ligated using polyethylene glycols.
Regarding claims 48-49 and 51, Zlatev teaches that a first RNA strand and a second RNA strand can be connected by a polyethylene glycol linker or a hexaethylene glycol linker (paragraph [0097]) joining the sugars of a nucleotide of the first RNA strand and of a nucleotide of the second RNA strand (paragraphs [0101]-[0103]). Hexaethylene glycol linker has the following structure:
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Hexaethylene glycol is a species of polyethylene glycol comprising 6 repeats of the ethylene glycol monomer, and comprises, as shown above, multiple OCH2CH2O structures (required by claim 51). Hexaethylene glycol comprises a chain of 42 covalently bonded atoms (required by claim 49). As Zlatev teaches that polyethylene glycol, generally, can be used as a non-nucleotide linker, an artisan would interpret that shorter polyethylene glycol linkers than hexaethylene glycol were obvious and encompassed by the teachings of Zlatev. Such encompassed PEG linkers would include pentaethylene glycol (5 repeats of the ethylene glycol monomer; a chain of 35 covalently bonded atoms) (required by claim 48).
Both ~914 and Zlatev teach that RNA nucleotides can be linked using non-nucleotide linkers, but ~914 does not teach specific non-nucleotide linker structures. Zlatev teaches that such linkers covalently linking RNA molecules can include polyethylene glycol linkers, including hexaethylene glycol, for the purpose of inhibiting separation of the linked strands in a cell (paragraph [0097]). It would have been obvious to an artisan to use the non-nucleotide linkers of Zlatev in the CRISPR system of ~914 as the non-nucleotide linkers claimed by ~914.
16994660:
Claims 27-33, 37-53 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 38-70 of copending Application No. 16994660 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
The copending application claims conjugate CRISPR-Cas protein-gRNAs, comprising an lgRNA-Cas protein (RNP) complex (claim 38). The copending application claims lgRNAs comprising spacer sequences targeting HIV genomic sequences (claim 42), HBV genomic sequences (claim 43), or herpesvirus genomic sequences (claims 44-45) (claim 46, spacer targets any genomic sequence). The copending application also claims the components and combinations of these components which result in the non-nucleotide linkers claimed in instant claim 43 (claim 39). The copending application claims the non-nucleotide internal linker anywhere within the guide RNA (claims 57, 65).
It would have been obvious to have arrived at any gRNA spacer sequence within the genomes of the viruses recited in the copending claims, including those of instant SEQ ID NOs:36-57 given that those of skill understand that spacer sequences are followed immediately by PAM sequence, thereby allowing one to scan nucleic acid sequences for various spacers which may be targeted by gRNAs. Thus claim 33 was prima facie obvious.
Regarding claims 37-42, the copending lgRNAs may be complexed with Cas9-peptide conjugates (claims 3, 33), and may be formulated with lipids or cell-penetrating peptides (claims 36-37).
The conjugates of the copending claims, when used as intended in the method of editing, will require introduction of the lgRNA into cells, thus obviating a method of preparing cells comprising the lgRNA, absent evidence to the contrary.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
17636857:
Claims 27-33, 37-42 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 39-56 of copending Application No. 17636857 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
The copending application claims conjugates of CRISPR-Cas protein-guide RNAs, comprising an lgRNA-Cas protein (RNP) complex and a lipid (claim 1). The copending application also claims a method of gene editing comprising delivering to targeted cells conjugates of CRISPR-Cas protein-lgRNA complex of claim 1; cleaving DNA to be edited, leading to a double strand break or a nick; hybridizing the resulting single DNA strand of the cleavage product with the 3’-homology arm of conjugated donor template and extending the 3’-end of complementary broken strand using said template to edit the target gene by introducing insertions, deletions, or point mutations included in the gene editing sequence of conjugated oligonucleotide (claim 44).
The method of copending claim 44 can be used for treatment of chronic viral infections by cleaving viral episomal, viral integrated DNA or both, leading to a double strand break or a nick; hybridizing one of the resulting single DNA strands of the cleavage product with the 3’-homology arm of conjugated donor template and extending the 3’-end of complementary broken strand using said template to deactivate the viral gene by introducing insertions, deletions, or point mutations included in the gene editing sequence (claim 45). The viral infection may be HBV, HIV, or a herpesviral infection (claim 46). It would have been obvious to have arrived at any gRNA spacer sequence within the genomes of the viruses recited in the copending claims, including those of instant SEQ ID NOs:36-57 given that those of skill understand that spacer sequences are followed immediately by PAM sequences, thereby allowing one to scan nucleic acid sequences for various spacers which may be targeted by gRNAs. Regarding claims 39-41, the portion of the specification supporting the claims indicates that the Cas protein of the invention can be a fusion protein (paragraph [0043]) and may comprise a CPP (paragraph [0272]).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
18218659:
Claims 27, 37-40, 42, 45-46 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of copending Application No. 18218659 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The copending application claims a method of directing a polypeptide to a target nucleic acid in a cell using a guide RNA that comprises one or more internal non-nucleotide linkers (claim 1). The guide RNA can be a component of a CRISPR RNP (claim 2). The polypeptide can be Cas9 (claim 8) or a fusion of Cas9 to another nuclease or any of a variety of other proteins (claim 9). The gRNA may comprise a lipid (claims 14, 20). The polypeptide (such as a Cas polypeptide) may comprise a nuclear localization peptide (claims 22, 25).
The copending application also claims a method of gene editing to modify a sequence by directing one or more polypeptides to said target nucleic acid using at least one guide RNA, wherein said guide RNA comprises one or more internal non-nucleotide linkers (claim 28). The internal non-nucleotide linker can be positioned between a crRNA and a tracrRNA, or within a tracrRNA (claims 3-4).
19084983:
Claims 27, 43-47, 50, 53 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19084983. Although the claims at issue are not identical, they are not patentably distinct from each other.
The copending application claims guide RNAs comprising a non-nucleotide linker in the spacer (claim 1), between the crRNA and the tracrRNA (claim 4) and within the tracrRNA (claim 5). Given that the purpose of gRNAs is to edit nucleic acid sequences in cells, and that the gRNAs of the copending application are intended for therapeutic gene editing (see title, “Guide RNA constructs for therapeutic gene editing”, emphasis added), it would have been obvious to have introduced such a gRNA into a cell to arrive at the invention of instant claims 27, 43-47, 50, 53.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 01/31/2026 have been fully considered but they are not persuasive. Applicant argued that the pending claims “are patentably distinct from Zhong’s claims”, as the claims of “Zhong” are directed to the lgRNA compound, and not methods of preparing cells comprising the lgRNA compound.
The applicant does not indicate which non-statutory double patenting rejection is referenced by “Zhong”, as all share the inventor “Zhong” and where labeled as “Zhong” in the prior office action.
As described in the rejections above, the copending and issued claims recite limitations explicitly claiming methods of introducing the lgRNA into cells (i.e., methods of preparing cells comprising the lgRNA), cells comprising the lgRNA (which necessitate any method of introducing the lgRNA into the cell, i.e. preparing the cell, as the lgRNA is not naturally occurring), or implicitly requiring that the lgRNA be introduced into cells. Furthermore, regarding copending application ~983, the title indicates the therapeutic application of the lgRNA, which necessitates, based on the known mechanism of action of a CRISPR gene editing system, introduction into cells, and thus these claims obviate cells comprising the claimed lgRNA. As the issued and copending claims over which the pending claims are rejected for non-statutory double patenting recite or render obvious cells comprising the claimed lgRNAs, the rejections are maintained.
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).
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/AFRICA M MCLEOD/ Examiner, Art Unit 1635
/KIMBERLY CHONG/ Primary Examiner, Art Unit 1636