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 without traverse of Group I (claims 1, 2, 17, 23, 25, 28, 33, 34, 43, 51, 57, 60, 62, 65) in the reply filed on 03/23/2026 is acknowledged.
Claims 70-71, 137, 140-141 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/23/2026.
Applicant’s election without traverse of an RNA of SEQ ID NO:106 (Species Group A), a polypeptide of SEQ ID NO:691 (Species Groups A, B), and VPR (Species Group B) in the reply filed on 03/23/2026 is acknowledged. However, the species election requirement of a guide RNA sequence of Table 2 and of an effector (e.g. VPR) of Species Group B is withdrawn. The species election requirement for a zinc finger protein sequence (e.g., SEQ ID NO:691) is maintained.
Claims Status
Claims 3-16, 18-22, 24, 26-27, 29-32, 35-42, 44-50, 52-56, 58-59, 61, 63-64, 66-69, 72-136, 138-139, 142-145 is/are cancelled. Claims 1-2, 17, 23, 25, 28, 33-34, 43, 51, 57, 60, 62, 65, 70-71, 137, 140-141 is/are currently pending with claims 70-71, 137, 140-141 withdrawn. Claims 1-2, 17, 23, 25, 28, 33-34, 43, 51, 57, 60, 62, 65 is/are under examination.
Information Disclosure Statement
The information disclosure statement filed 08/10/2023 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 and struck through has not been considered. No foreign patent documents were provided with the IDS filed 08/10/2023.
The information disclosure statement filed 03/23/2026 fails to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. It has been placed in the application file, but the information referred to therein and struck through has not been considered. Two of the three NPL documents provided appear to be written in a Chinese language. No English statement of relevance, English abstract, or English translation were provided for either document. It is not possible to determine whether these two Chinese documents are NPLs 1 and 3 as listed in the IDS.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. Hyperlinks were found on page 1 line 25 and page 24 line 5. Applicant is advised to review the specification in order to ensure that all hyperlinks are identified and appropriately removed.
Claim Objections
Claim 51 is objected to because of the following informalities:
Claim 51 recites “the second fusion” in lines 2-3 in reference to the second fusion protein. For clarity, “the second fusion” should be amended to “the second fusion protein”.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-2, 25, 28 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (a product of nature) without significantly more. The claim(s) recite(s) a site-specific FOXP3 disrupting agent targeting a FOXP3 expression control region, encompassing naturally-occurring transcriptional repressors of FOXP3 gene. This judicial exception is not integrated into a practical application because the claims do not recite additional elements which amount to more than the judicial exception. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because no such additional elements are recited, nor does it meet any other considerations under MPEP 2106.05(a-h). The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception. The only required elements recited in claims 1-2, 25, and 28 are that the FOXP3 disrupting agent targets a FOXP3 expression control region, comprises a FOXP3 targeting moiety (claim 1), comprises a polypeptide or a modification (claim 2), is comprised in a cell (claim 25), and is comprised in a composition (claim 28), all of which requirements encompass naturally-occurring FOXP3 transcriptional repressors expressed by cells.
Claims 1-2, 25, 28 recite a site-specific FOXP3 disrupting agent, which constitutes a composition—one of the statutory categories of invention.
Claims 1-2, 25, and 28 recite products which encompass products of nature as described in MPEP § 2106.04(b)(II). These recited compositions encompass naturally-occurring proteins which specifically bind to sequences within the expression control region of the FOXP3 gene (Haiqi, 2011; proteins such as NFAT, AP1, STAT5, RUNX, Smad3, and CREB were known to bind to the expression control region of the FOXP3 gene and disrupt expression of FOXP3). The specification teaches that a “site-specific FOXP3 disrupting agent” “refers to any agent that specifically binds to a target FOXP3 expression control region and, e.g., modulates expression of a FOXP3 gene” (page 15 lines 19-21).
According to Step 2A, Prong Two, set forth in MPEP § 2106.04(II)(A)(2), the claims are next evaluated with respect to whether the judicial exception is integrated into a practical application. These considerations are set forth in MPEP § 2106.05(a)-(h). This analysis turns to the additional steps or elements recited within the claims. Claims 1-2, 25, and 28 do not recite any additional steps or elements beyond what has been determined to be a judicial exception.
There are no additional elements that reflect an implementation with a particular additional element nor is it transformed or reduced to a different state, nor which meets any other considerations under MPEP § 2106.05(a)-(h), such that the claimed product amounts to significantly more than the judicial exceptions.
For all these reasons, claims 1-2, 25, and 28 are directed to judicial exceptions without significantly more and are rejected.
Claims 25 and 62 are rejected under 35 U.S.C. 101 because Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claims 25 and 62 are rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101). Claims 25 and 62 are drawn to any cell in any environment (in vivo, in vitro, ex vivo) comprising the claimed compositions. The specification (pages 86-87) teaches that the claimed compositions may be introduced into human cells; the specification further teaches (page 2) that the compositions may be administered to subjects (in vivo). As such, the cell of claims 25 and 62 is interpreted to encompass cells in a human organism, constituting part of a complete human organism.
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 1-2, 17, 33-34, 43, 51, 57 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 2 recites “The site-specific FOXP3 disrupting agent of claim 1, (a) wherein the site-specific FOXP3 targeting moiety comprises a polymeric molecule; optionally a polyamide or a polynucleotide” (lines 1-3). It is unclear whether the polymeric molecule comprises or consists of a polyamide or a polynucleotide, as the phrase “optionally a polyamide or a polynucleotide” does not indicate as such.
The term “about” in claims 1, 17, 43, 51, 57 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Page 14 lines 15-19 states that the term “’about’ can be understand as about 2 standard deviations from the mean. In certain embodiments, about means ±10%” (emphasis added). The definition of the term “about” given in the specification merely provides examples of what “about” could mean, but does not provide a limiting definition. As such, the metes and bounds of the term “about” and values modified by the term “about” are unclear.
Claim 17 recites “the entire nucleotide sequence of any one of the nucleotide sequences in Table 2”, incorporating all nucleic acid sequence elements of Table 2 (lines 3-4). Claims 17 (line 14) and 34 (line 7) recite “the amino acid sequences listed in Table 1B”. According to MPEP § 2173.05(s), “where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).” Appropriate correction is required, including the removal of references to a table.
Claim 33 recites “the fusion protein comprising a site-specific FOXP3 targeting moiety which targets a FOXP3 expression control region and an effector molecule” (lines 2-3). It is unclear based on this phrasing whether the fusion protein comprises the effector molecule, or if the effector molecule is targeted by the targeting moiety.
Claim 34 contains the trademark/trade name TALEN. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe transcription activator-like effector (TALE) nuclease and, accordingly, the identification/description is indefinite.
Claim 51 recites the limitations "the second fusion [protein]”, “the fusion protein”, “the second FOXP3 expression control region”, “the FOXP3 expression control region”, “the effector”, “the second effector”. There is insufficient antecedent basis for this limitation in the claim. A second fusion protein is a fusion protein; a second FOXP3 expression control region is a FOXP3 expression control region; a second effector is an effector. It is not clear which fusion protein, FOXP3 expression control region, or effector is referred to by “the fusion protein”, “the FOXP3 expression control region”, or “the effector” in claim 51. Referring to the fusion proteins as “first fusion protein” and “second fusion protein”, and likewise referring to the different effectors and FOXP3 expression control regions, would be remedial.
Claim 51 recites that “the second effector is different than the [first] effector” and “the second effector is the same as the [first] effector” (lines 6-7 and “and/or” line 12). It is not possible for two molecules to be the same and different. As such, the metes and bounds of claim 51 are unclear and indefinite.
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 1-2, 17, 23, 25, 28, 33-34, 43, 51, 57, 60, 62, 65 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”).
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 34 recites a “peptide-nucleic acid fusion” (line 9). However, the disclosure does not describe the structure or qualities of a peptide-nucleic acid fusion, nor does the disclosure provide any species of peptide-nucleic acid fusion. An artisan would therefore not be able to determine that the applicants were in possession of any peptide-nucleic acid fusion.
Claim 34 recites that the effector molecule “comprises a nucleic acid molecule encoding a polypeptide”, “is selected from the group consisting of a nuclease, a physical blocker, an epigenetic recruiter, and an epigenetic CpG modifier, and combinations of any of the foregoing”, “comprises a CRISPR associated protein (Cas) polypeptide or nucleic acid molecule encoding the Cas polypeptide”, “comprises a zinc finger polypeptide” and/or “comprises a Transcription activator-like effector nuclease”. The disclosure does not describe or provide species of effector molecules which comprise a combination of more than one of: a Cas nuclease, a zinc finger polypeptide, a TALE nuclease, a physical blocker, an epigenetic recruiter, and an epigenetic CpG modifier. Furthermore, the disclosure does not provide a description or species of effector molecule which comprises both a nucleic acid molecule encoding a polypeptide and a polypeptide. As such, claim 34 is only supported by the disclosure when each of (a)-(i) is in the alternative (“or”, not “and” in line 21).
Claim 43 recites that the transcriptional enhancer is a VPR and a p300 (“and/or”, line 15). The disclosure only provides a description of and a species of a VPR transcriptional enhancer and a p300 transcriptional enhancer separately, not joined in the same molecule. As such, the disclosure only supports the term “or” in line 15, not “and”, as “and” would require that the transcriptional enhancer be both a VPR and a p300.
Claim 57 recites that the site-specific FOXP3 disrupting agent comprises both a dCas-p300 and a dCas-VPR (“and/or” line 41). The disclosure only provides a description of and a species of a VPR transcriptional enhancer and a p300 transcriptional enhancer separately, not joined in the same disrupting agent. As such, the disclosure only supports the term “or” in line 41, not “and”, as “and” would require that the disrupting agent comprise both a VPR and a p300.
Claim 17 recites a genus of nucleic acid sequences at least 85% identical to any guide RNA sequence in Table 2; claims 17 and 34 recite a genus of polypeptides having amino acid sequences at least 85% identical to any amino acid sequence of Table 1B; claim 43 recites a genus of transcriptional enhancers having amino acid sequences at least 85% identical to SEQ ID NO:64 or 65; claims 51 and 57 recite a genus of fusion proteins having sequences at least 85% identical to SEQ ID NOs 10-11 or encoded by sequences at least 85% identical to SEQ ID NOs:7-8.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. In the instant case, SEQ ID NOs:80-94, 142-608 are the only species of zinc finger proteins, SEQ ID NOs: 96-113 are the only species of guide RNA, SEQ ID NOs:10-11 (and encoding sequences SEQ ID NOs:7-8) are the only species of fusion proteins, and SEQ ID NOs:64-65 are the only species of transcriptional enhancers whose complete structures are disclosed. While the genera each encompass large numbers of variants and molecules that have the same activity (binding Cas9 and guiding the complex to a target sequence, for a guide RNA; binding target DNA sequences, for zinc finger proteins and Cas9 fusion proteins; transcriptional enhancement, for transcriptional enhancers) and the genera encompass large numbers of variants and molecules that have different structures, the specification does not describe the complete structure of representative numbers of species of each large genus of molecules or functional equivalents thereof. Additionally, the specification does not describe the complete structure of a representative number of species of the large genus of modified guide RNAs, Cas9 fusion proteins, transcriptional enhancers, and zinc finger proteins. Furthermore, while the claims (claims 17, 34) recite that TALE polypeptides may be used in the invention, no TALE polypeptide sequences are disclosed in the specification. While the disclosure asserts that “the design and preparation of such TALE polypeptides which specifically bind to a DNA target region of interest, such as FOXP3 expression control region, is well known in the art” and that modification of specific amino acid residues corresponds with DNA recognition specificity (page 81 lines 1-11), it does not teach specific species of TALE proteins are described, the specific DNA sequences targeted by the TALE proteins, nor the specific residue alterations required to target these target sequences.
Next, then, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics (i.e. other than nucleotide sequence), specific features and functional attributes that would distinguish different members of the claimed genus. In the instant case, the only other identifying characteristics are: that guide RNAs comprise sequences complementary to a target sequence, can bind a nuclease, and can direct binding of the nuclease to a target sequence (page 81); that Cas9 proteins bind to guide RNA and as a result, bind to target sequences (pages 81-82); that zinc finger proteins bind to DNA (pages 30-33); and that a transcriptional enhancer increases gene transcription (page 16 line 28). Such a functional limitation cannot be an identifying characteristic for the claimed diverse genus of molecules since by Applicant’s definition of these genera of molecules or functional equivalent thereof, all members of each claimed genera will have the corresponding characteristic. Further, no identifying characteristics of the modified gRNA, Cas9 proteins, zinc finger proteins, or transcriptional enhancers are disclosed.
The inventions of claims 1-2, 23, 25, 28, 33, 51, 60, 62, 65 broadly encompass the use of the inventions of claims 17, 34, 43, 51, and 57, and claim 43 requires the use of the inventions of claim 34, and therefore are likewise rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement.
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) 1-2, 23, 25, 28, 33-34, 43, 51, 57, 60, 62, 65 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gersbach (WO2018031762A1).
Regarding claim 1, Gersbach teaches a site-specific FOXP3 disrupting agent, comprising a site-specific FOXP3 targeting moiety which targets a FOXP3 control region (the FOXP3 promoter) (claims 1-4, 7, 9).
Regarding claim 2, Gersbach teaches that the site-specific FOXP3 targeting moiety comprises a polypeptide (a fusion protein) and a polynucleotide (a guide RNA) (claim 1). Gersbach teaches that the target sequence is upstream of the FOXP3 transcription start site (claims 4-9). Gersbach teaches that the disrupting agent comprises a modification (claim 16, the fusion protein is modified to be nuclease-dead).
Regarding claim 23, Gersbach teaches a vector encoding the FOXP3 disrupting agent (paragraph [0081]).
Regarding claim 25, Gersbach teaches a cell comprising the FOXP3 disrupting agent (claim 28).
Regarding claim 28, Gersbach teaches that the FOXP3 disrupting agent may be present in a pharmaceutical composition (paragraphs [00133]-[00134]).
Regarding claims 33-34, 43, 51, and 57, Gersbach teaches that the site-specific FOXP3 disrupting agent comprises a dCas9-p300 fusion protein and one or more guide RNAs targeting different sequences in the FOXP3 expression control region, and wherein the dCas9-p300 fusion protein comprises SEQ ID NO:26 (SEQ ID NO:26 is 97.6% identical to instant SEQ ID NO:10 and comprises a p300 sequence 100% identical to instant SEQ ID NO:65, see alignments below) (claims 1-13, 15, 19, 27).
SEQ ID NO:26 vs instant SEQ ID NO:10:
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Regarding claim 60, Gersbach teaches a vector encoding the FOXP3 disrupting agent (paragraph [0081]).
Regarding claim 62, Gersbach teaches a cell comprising the FOXP3 disrupting agent (claim 28).
Regarding claim 65, Gersbach teaches that the FOXP3 disrupting agent may be present in a pharmaceutical composition (paragraphs [00133]-[00134]).
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) 1-2, 17, 23, 25, 28, 33-34, 43, 51, 57, 60, 62, 65 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gersbach (WO2018031762A1), in view of Joung (US20160024524A1).
Regarding claim 1, Gersbach teaches a site-specific FOXP3 disrupting agent, comprising a site-specific FOXP3 targeting moiety which targets a FOXP3 control region (the FOXP3 promoter) (claims 1-4, 7, 9).
Regarding claim 2, Gersbach teaches that the site-specific FOXP3 targeting moiety comprises a polypeptide (a fusion protein) and a polynucleotide (a guide RNA) (claim 1). Gersbach teaches that the target sequence is upstream of the FOXP3 transcription start site (claims 4-9). Gersbach teaches that the disrupting agent comprises a modification (claim 16, the fusion protein is modified to be nuclease-dead).
Regarding claim 17, Gersbach teaches that the FOXP3 targeting moiety comprises a guide RNA sequence of SEQ ID NO:14 (SEQ ID NO:14 is 100% identical to the first 20 nucleotides of instant SEQ ID NO:109, of Table 2, which first 20 nucleotides are indicated in Table 2 as complementary to the target sequence, see alignment below) (claim 11). Gersbach also teaches that the complementary region of the gRNA is 12-22 nucleotides long, obviating truncations of SEQ ID NO:14 resulting in a 20-nucleotide-long sequence in place of the 23-nucleotide-long sequence of SEQ ID NO:14 (claim 10).
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Regarding claim 23, Gersbach teaches a vector encoding the FOXP3 disrupting agent (paragraph [0081]).
Regarding claim 25, Gersbach teaches a cell comprising the FOXP3 disrupting agent (claim 28).
Regarding claim 28, Gersbach teaches that the FOXP3 disrupting agent may be present in a pharmaceutical composition (paragraphs [00133]-[00134]).
Regarding claims 33-34, 43, 51, and 57, Gersbach teaches that the site-specific FOXP3 disrupting agent comprises a dCas9-p300 fusion protein and one or more guide RNAs targeting different sequences in the FOXP3 expression control region, and wherein the dCas9-p300 fusion protein comprises SEQ ID NO:26 (SEQ ID NO:26 is 97.6% identical to instant SEQ ID NO:10 and comprises a p300 sequence 100% identical to instant SEQ ID NO:65, see alignments below) (claims 1-13, 15, 19, 27). Gesrbach also teaches that this dCas9 sequences corresponds to S. pyogenes Cas9 (paragraph [0088]).
SEQ ID NO:26 vs instant SEQ ID NO:10:
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Regarding claim 60, Gersbach teaches a vector encoding the FOXP3 disrupting agent (paragraph [0081]).
Regarding claim 62, Gersbach teaches a cell comprising the FOXP3 disrupting agent (claim 28).
Regarding claim 65, Gersbach teaches that the FOXP3 disrupting agent may be present in a pharmaceutical composition (paragraphs [00133]-[00134]).
However, Gersbach does not teach the tracrRNA sequence of the guide RNA required for the guide RNA to bind to the Cas9 nuclease (required by claim 17; the guide RNA sequences of Table 2 each comprise a crRNA and a tracrRNA).
Joung teaches single guide RNA (sgRNA) comprising a crRNA sequence complementary to a target sequence and 20 nucleotides long, and a tracrRNA sequence.
Regarding claim 17, Joung teaches that an sgRNA for use with S. pyogenes Cas9 (paragraphs [0094], [0132]) comprises a 17-20 nucleotide-long crRNA sequence (sequence complementary to a target sequence) linked at its 3’ terminus to a tracrRNA of SEQ ID NO:15 (Fig. 1; paragraphs [0071]-[0072]; claims 3, 11, 14, 29).
Gersbach does not teach any particular tracrRNA sequence (either separate or in the same sgRNA as the described crRNA sequences). However, Gersbach does teach that Type II effector systems such as Cas9 systems require a tracrRNA and a crRNA, either as separate molecules or joined in an sgRNA (paragraphs [0085]-[0087]). An artisan would look to the prior art regarding S. pyogenes Cas9 systems to determine an appropriate tracrRNA sequence for the sgRNAs described by Gersbach. Joung teaches multiple tracrRNA sequences usable with an S. pyogenes Cas9 system, and an artisan would find it obvious to use such tracrRNA sequences with the S. pyogenes Cas9 system of Gersbach. As Cas9 requires a tracrRNA sequence in order to bind to a guide RNA, it would have been obvious to an artisan that the addition of the tracrRNA sequence of Joung to the gRNA of Gersbach would enable the gRNA of Gersbach to bind to the Cas9 of Gersbach and direct editing of the FOXP3 expression control region.
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.
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, 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).
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/AFRICA M MCLEOD/ Examiner, Art Unit 1635
/KIMBERLY CHONG/ Primary Examiner, Art Unit 1636
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