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 190, 192, 195-196, 198, 201-202 which now include new claims 210-217, in the reply filed on 8/4/2025 is acknowledged.
Claims 203-209 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/4/2025.
For the species election, Applicant elects gRNAs targeting intron 2 of a BCL11A gene which comprise SEQ ID NOs as claimed in claims 195 and 201.
Claims status
Claims 191, 193, 194, 197, 199, 200, 205, 206 is/are cancelled and claims 210-217 is/are newly added. Claims 190, 192, 195-196, 198, 201-202, 203, 204, 207- 209, 210-217 is/are currently pending with claims 203, 204, 207-209 is/are withdrawn. Claims 190, 192, 195-196, 198, 201-202, 210-217 is/are under examination.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) or under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 61/970,588, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The disclosure in `588 does not provide support for the claims 190, 192, 195-196, 198, 201-202, 210-217 that specifically recite targeting intron 2 of the BCL11A gene. The disclosure in `588 does not disclose intron 2 of BCL11A gene (as instantly recited in claims 190, 196) or the enhancer region within this intron (as instantly recited in claims 192, 198) or the specifically recited DHS sites of claims 210-217. Furthermore, none of the sequences claimed in claims 195 and 201 were disclosed in `588.
The disclosure of the prior-filed application, Application No. 62/084,487, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The disclosure in `588 does not provide support for the claims 195 and 201, specifically the sequences of SEQ ID NO: 15552-16009, 16261-16279 are not disclosed. Some of these sequences may have been recited in Tables 7 of `487 because at least some of the sequences of SEQ ID NO: 15552-16009, 16261-16279 appear to be duplicates of SEQ 4835-4980 of Table 7 of `487. For example, SEQ ID NO 15604 is the same as SEQ ID NO 16261 which is the same as SEQ ID NO 4838 and SEQ ID NO 15605 is the same as SEQ ID NO 16262 which is the same as SEQ ID NO 4835. However, there are about 150 sequences in SEQ ID NOs: 4835-4980 but there are more than 550 sequences in SEQ ID NO: 15552-16009, 16261-16279. Thus, it is concluded that several sequences in SEQ ID NO: 15552-16009, 16261-16279 as claimed are not supported by `487.
Taken together, claims 190, 192, 196, 198, 202, 210-217 have priority date of 11/25/2014 based on Application No. 62/084,487. Claims 195 and 201 have priority date of 3/26/2015 based on Application No. PCT/US2015/022856.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
At least some of the more than 600 claimed sequences are duplicates. For example, SEQ ID NO 15604 is the same as SEQ ID NO 16261 which is the same as SEQ ID NO 4838 and SEQ ID NO 15605 is the same as SEQ ID NO 16262 which is the same as SEQ ID NO 4835. Applicant is requested to identify sequences in SEQ ID NO: 15552-16009, 16261-16279 that are duplicates of SEQ 4835-4980.
Claim Rejections - 35 USC § 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 210-217 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.
Claims 210 and 214 each recite “the targeting domain” of the gRNA of claims 190 and 196 respectively “is between +52.0 to +64.4 kilobases (kb) from a Transcription Start Site (TSS+52kb to TSS+64.4kb)”. Since gRNAs are generally less than 100 bases, it is unclear how the targeting domain could be 52-64 kilobases from another site in the gRNA and what a TSS is in reference to a gRNA. Even for the nucleic acid of claim 214, it is unclear if the nucleic acid is required to encode another transcript that has a TSS which is 52-64 kilobases from the targeting domain of the gRNA. A target domain in the intron 2 of BCL11A gene which is +52.0 to +64.4 kilobases (kb) from the TSS of BCL11A gene is disclosed in the specification (Figure 10). Therefore, for the purpose of compact prosecution, the claim(s) 210 and 214 is/are interpreted as “the target
Claim 211-213 and 215-217 is/are rejected due their dependence on claims 210 and 214 respectively because they do not clarify the 112b issue noted with claims 210 and 214.
Claim Rejections - 35 USC § 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 195 and 201 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.
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and what Applicant has possession of.
Claims 195 and 201 each recite the “targeting domain comprises or consists of a sequence that is the same as, or differs by no more than 3 nucleotides from, a targeting domain sequence consisting of a sequence selected from” the recited SEQ IDs. The broadest reasonable interpretation of the phrase ‘a sequence selected from [another sequence]’ embraces fragments comprised within the another sequence, such as the recited SEQ IDs in the instant case. Therefore, the claims embrace targeting domain sequences that are any fragment of any of the recited SEQ IDs.
The specification discloses SEQ ID No: 4835-4980, 15598-16009 and 16261-16279 as 17 or 20 nucleotide sequences that are exactly complementary to a target domain in intron 2 of BCL11A gene (Table 7A-D, 8A-D, 21A-D, 22A-E, 23A-C, 31). The specification discloses SEQ ID No: 15552-16009 as 17 or 20 nucleotide sequences that are exactly complementary to target domain that is not in intron 2 but 500bp downstream of BCL11A gene TSS i.e. in intron 1 (Table 20A-C). The targeting domain of a sgRNA functions to target the sgRNA to a target domain in the gene of interest, which is intron 2 of BCL11A gene in the instant case. This is also evident from the claim that requires the targeting domain to be complementary to a target domain. Furthermore, it was known in the art that sgRNA targeting domains are required to be of a minimum specific length, generally around 20nt, with a minimum complementarity requirement based on the associated Cas enzyme (generally no less than 3bp). See para 1 and 2 from Xie et al (Molecular plant 7.5 (2014): 923-926). Therefore, for a sequence to function as a targeting domain in a sgRNA it is required to be at least about 20nt. However, in claiming “a sequence selected from” the recited SEQ IDs, the claims embrace targeting domain sequences that comprise fragments of any length of the recited SEQ IDs, such as a 2nt fragment comprised in the targeting domain.
The specification does not disclose any fragment of any of the recited SEQ IDs which could functions as a sgRNA targeting domain to target intron 2 of BCL11A gene. Fragments of SEQ ID NO: 4835-4980, 15552-16009 and 16261-16279 can vary substantially. There is no teaching in the specification in which any fragment of any of the recited SEQ IDs retains the ability of the sequence to function as a sgRNA targeting domain. Consequently, there is no information about which nucleotides are required in the claimed SEQ IDs to function as the sgRNA targeting domain.
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).
Further, the breadth of the genus of fragments of SEQ ID NOs: 4835-4980, 15552-16009 and 16261-16279 lack a written description.
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 Deutschland 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.").”
In the instant case, the species disclosed are identical to the claimed recited SEQ IDs. No fragment that could represent a species for the genus of fragments embraced is disclosed. There is no identification of any particular portion of the structure that must be conserved such that the embraced fragments could be envisioned. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the fragments embraced by recited genus.
Therefore, the claimed invention is not adequately described. The claims require essential or critical elements which are not adequately described in the specification, and are not conventional in the art before the effective filing date.
Claim Rejections - 35 USC § 112(d)
Improper Dependence Rejection
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 195 and 201 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 195 depends from claim 190 which requires the gRNA to comprise a targeting domain limited to target sequences in intron 2 of BCL11A gene. However, claim 195 broadens the gRNA of claim 190 by reciting targeting domains that target sequences outside of intron 2 of BCL11A gene. Specifically, SEQ ID NOs: 15552-16009 are disclosed as targeting 500bp downstream of BCL11A gene TSS i.e. NOT intron 2 (Table 20A-C).
Similarly, due to the recitation of SEQ ID NOs: 15552-16009 in claim 201, it broadens the gRNA of claims 196 that is limited to target sequences in intron 2 of BCL11A gene.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Improper Markush Rejection
Claims 195 and 201 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
Members of a Markush group share a "single structural similarity" when they belong to the same recognized physical or chemical class or to the same art-recognized class. A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved.
The Markush grouping of gRNAs comprising a targeting domain comprising or consisting of SEQ ID NO: 4835-4980, 15552-16009 and 16261-16279 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
The “gRNAs” recited as alternatives (i.e. comprising a targeting domain comprising or consisting of SEQ ID NO: 4835-4980, 15552-16009 and 16261-16279) are each nucleic acids however they do not belong to a “recognized physical class, a recognized chemical class, or an art-recognized class” because the expectation from the knowledge in the art did not recognize these molecules to behave in the same way in the context of the claimed invention. The molecules claimed as gRNAs are not functionally equivalent because their targeting domains are not functionally equivalent. These targeting domains target distinct regions in the BCL11A gene and critically, are restricted to function with distinct Cas enzymes such that these molecules could not be substituted one for the other, with the expectation that the same intended result would be achieved.
The specification discloses that gRNAs comprising domains of SEQ ID No: 4835-4886, 15598-15605, 16261-16279 are restricted to function with Cas9 enzyme from S. pyogenes because of the specific PAM sequence required by the Cas9 enzyme from S. pyogenes (SpCas9; in Tables 7A-D, 21A-D, 31). Furthermore, these molecules target intron 2 of BCL11A gene. Thus, the use of these molecules is restricted to use with SpCas9 when targeting intron 2 of BCL11A gene.
The specification discloses that gRNAs comprising domains of SEQ ID No: 4887-4978, 15659-16001 are restricted to function with Cas9 enzyme from S. aureus because of the specific PAM sequence required by the Cas9 enzyme from S. aureus (SaCas9; in Tables 8A-D, 22A-E). Furthermore, these molecules target intron 2 of BCL11A gene. Thus, the use of these molecules is restricted to use with SaCas9 when targeting intron 2 of BCL11A gene.
The specification discloses that gRNAs comprising domains of SEQ ID No: 4979-4980, 16002-16009 are restricted to function with Cas9 enzyme from N. meningitidis because of the specific PAM sequence required by the Cas9 enzyme from N. meningitidis (NmCas9; in Tables 9, 23A-C). Furthermore, these molecules target intron 2 of BCL11A gene. Thus, the use of these molecules is restricted to use with NmCas9 when targeting intron 2 of BCL11A gene.
Finally, the specification discloses that gRNAs comprising domains of SEQ ID No: 15552-15597 are restricted to function with Cas9 enzyme from N. meningitidis because of the specific PAM sequence required by the Cas9 enzyme from N. meningitidis (NmCas9; in Tables 20A-C). Furthermore, these molecules target 500bp downstream of BCL11A gene TSS which is not in intron 2 but instead intron 2. Thus, the use of these molecules is restricted to use with NmCas9 when targeting intron 1 of BCL11A gene.
Taken together, these molecules belong to distinct classes of molecules that could not be substituted one for the other, with the expectation that the same intended result would be achieved. This because these molecules are restricted to function with distinct enzymes, with distinct properties and target distinct regions in the BCL11A gene resulting in distinct outcomes.
Furthermore, these molecules do not have a substantial structural feature from which a common use flows. The gRNAs for SpCas9, SaCa9 and NmCas9 have distinct structures and target distinct PAM sequences (page 107, para 2).
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim interpretation
On page 67, the specification defines “A gRNA molecule, as that term is used herein, refers to a nucleic acid that promotes the specific targeting or homing of a gRNA molecule/Cas9 molecule complex to a target nucleic acid”.
Claim 192 and 198 recite gRNAs comprising targeting domain “configured to” target an enhancer region of the BCL11A gene. These claims depend from claim 190 and 196 respectively, that each require the targeting domain to be complementary to a target domain in intron 2 of BCL11A gene. Thus, the phrase “configured to” in claims 192 and 198 are interpreted such that the targeting domains are configured to a target due to complementarity to the target. Furthermore, since claim 190 and 196 require the target domain to be in intron 2 of BCL11A gene, it is interpreted that the “enhancer region” recited in claims 192 and 198 are enhancer regions within intron 2 of BCL11A gene. These claims maybe amended to reflect this interpretation in the following way: “wherein said targeting domain is complementary to the target domain in an enhancer region within intron 2 of the BCL11A gene”.
Similarly, for claims 210-217, in addition to the interpretation presented in 112b rejection, it is further interpreted that the TSS+52kB to TSS+64.4kb is a region within intron 2 of BCL11A gene.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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) 190, 192, 195, 196, 198, 201, 210-217 is/are rejected under 35 U.S.C. 103 as being unpatentable over Canver et al (THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 289, NO. 31, pp. 21312–21324, August 1, 2014) in view of Bauer et al (SCIENCE VOL 342 11 OCTOBER 2013; IDS 4/21/2022) and BCL11A gene from hg19 RefSeq (Genome assembly GRCh37; Feb 2009, available through UCSC Genome Browser; Sequence for BCL11A gene from hg19 attached in PTO-892).
Regarding claims 190, 196 and 202, Canver teaches plasmid pSpCas9(BB) i.e. a nucleic acid in which sequences encoding gRNA molecules that target intronic sequences within a genome are cloned into and comprises sequences encoding SpCas9, as required by claim 202 (Figure 1A, Experimental Procedures: CRISPR Design and Creation). Canver teaches that “A strategy of using two DSBs to create a deletion of the intervening segment by NHEJ has previously been successfully applied using zinc finger nucleases, TAL effector nucleases, and CRISPR systems (6, 20–25). However, the efficiency, reliability, and genomic outcomes of using pairs of CRISPRs to introduce genomic deletions remain incompletely characterized. Here, we sought to test the capability and efficiency of creating deletions in mammalian cell lines. Our results indicate that the CRISPR/Cas9 system is a powerful tool for the robust and dependable generation of genomic deletions.” (page 21313, col. 1, para 2). Herein reference 21 is Bauer et al (SCIENCE VOL 342 11 OCTOBER 2013).
Canver exemplifies the use of CRISPR/Cas9 system that uses gRNAs by targeting distinct sequences (exonic, intronic, intergenic) in different loci on different chromosomes (Figure 1A, B).
Canver teaches methods to design gRNAs and nucleic acids encoding the gRNA. On page 21312, col. 2, para 1, Canver teaches that for SpCas9 sgRNA “Site-specific cleavage is directed by complementarity of the sgRNA to a 20-bp genomic sequence (protospacer) immediately 5’ of a protospacer-adjacent motif (PAM), which is NGG for SpCas9”. In the Experimental Procedures: CRISPR Design and Creation, Canver teaches that using RefSeq (human genome sequence from NCBI) and publicly available on-line tools, sgRNAs can be designed with minimized off-target effects which can be cloned into Cas9 encoding plasmid pSpCas9(BB). Referencing Bauer again, Canver teaches that “The CRISPR-mediated deletion strategy appears particularly suited for the study of noncoding regulatory DNA where frame-shift
mutations do not pertain (21)” (page 21323, col. 2, para 4).
Canver does not explicitly teach targeting an enhancer region within intron 2 of BCL11A gene (as recited in claims 190, 192, 196, 198), specifically wherein the enhancer region comprises the DNAse 1 hypersensitivity sites of TSS+55kb, TSS+58kb or TSS+62kB (as recited in claims 210-217). Thus, Canver does not explicitly teach a gRNA with a targeting domain complementary to an enhancer region within intron 2 of BCL11A gene that comprises the DNAse 1 hypersensitivity sites of TSS+55kb, TSS+58kb or TSS+62kB or the specifically recited sequences for the targeting domain in claims 195 and 201.
However, these regions and targeting these regions by TAL-effectors, as already mentioned by Carver, was taught by Bauer.
Bauer teaches that TSS+55kb, TSS+58kb or TSS+62kB sites in the BCLA11 gene are DNAse 1 hypersensitivity sites in intron 2 of this gene and these are enhancer regions (Figure 1; page 254, col. 2, para 1, and col. 3, para 1; as required by claims 190, 192, 196, 198, 210-217).
Furthermore, Bauer also teaches targeting these enhancer regions using TALEN-based genome engineering technique in a mouse cell wherein a TALEN pair was used to target +50kbTSS and +60.4kbTSS to delete the target region within TSS+52kb to TSS+64.4kb (Figure S7; Supplementary: Materials and Methods: TALEN-mediated chromosomal deletion). Bauer teaches that deletion of the enhancer region increases embryonic globin expression and thus shows its utility for treatment of sickle cell disease (Figure S9).
The chromosomal locations taught by Bauer are in reference to hg19 human genome reference sequence (Supplementary: Materials and Methods: Fine-mapping BCL11A locus).
hg19 Ref Seq teaches the sequence for the entire BCL11A gene, including the sequence for intron 2 and the location of DHS sites within this intron is taught by Bauer (see BCL11A gene sequence from hg19 with intron 2 start and end sites highlighted in blue in PTO-892).
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the method of Canver to design a gRNA that comprises a targeting domain complementary to a target domain in intron 2 of BCL11A gene, such that the gRNA targets the DHS sites in the enhancer region in intron 2 in the BCLA11 gene (such as TSS+55kb, TSS+58kb or TSS+62kB), as taught by Bauer and sequence taught by hg19 RefSeq. Such a design would predictably yield a gRNA molecule as claimed. An ordinary artisan would be motivated to design such a gRNA because Canver teaches CRISPR/Cas9 systems, that use gRNAs, are a powerful tool for robust and dependable generation of genomic deletions and can be used as alternatives to methods such as taught by Bauer where TALENs was used to target BCL11A DHS sites in intron 2. An ordinary artisan reasonably expects to generate a gRNA targeting BCL11A intron 2 DHS sites because Canver teaches methods to design gRNAs using publicly available tools such publicly available genomic sequences (such as RefSeq) and gRNA selection tools, Bauer teaches the chromosomal location of each of the DHS sites in the BCL11A intron 2 (Supplementary: Materials and Methods: Fine-mapping BCL11A locus) and hg19 taught the sequence for intron 2 of BCL11A gene. Specifically, Canver taught the method to design gRNAs that have a 20bp targeting domain complementary the target domain that is next to a NGG PAM sequence for a SpCas9-gRNA (page 21312, col. 2, para 1). An ordinary artisan would reasonably expect to use this method to identify target domains in intron 2 of BCL11A gene resulting in several targetable domains which would be the same as listed in claim 195 and 201. An ordinary artisan would identify target sequences complementary to SEQ ID NOs 16261 and 16262 that are upstream of a NGG PAM within intron 2 and thus design gRNAs comprising SEQ ID NOs 16261 and 16262 to target these sequences in intron 2, amongst other testable gRNA sequences. A list of targetable domains could be identified using Canver’s method and hg19 BCL11A intron sequence, such as the several listed in claims 195 and 201 without requiring any inventive ingenuity.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
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.
Claims 190, 192, 195-196, 198, 201-202, 210-217 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 12, 21 of U.S. Patent No. 11,242,525. Although the claims at issue are not identical, they are not patentably distinct from each other.
Claims 1, 12 in `525 are methods of altering a cell that disclose a gRNA with the structure that is identical to the claimed gRNA and a Cas9 molecule. Claims 1, 12 in `525 discloses a gRNA that comprises a targeting domain with SEQ ID NOs 16261-16279. These sequences are identical to instantly claimed sequences in claims 195 and 201 which target DHS enhancer region in intron 2 of BCL11A gene, as recited in claims 190, 192, 196, 198, 210-217. Claim 21 in `525 further recite the gRNA and Cas9 are encoded by a nucleic acid, as instantly claimed for claims 196, 198, 201, 214-217. Therefore, in teaching a method that uses the instantly claimed gRNA and a nucleic acid encoding the claimed gRNA, claims 1, 12 and 21 in `525 render obvious the instantly claimed gRNA and nucleic acid encoding the claimed gRNA.
Claims 190, 192, 196, 198, 210-217 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11, 13-17 of U.S. Patent No. 11,963,982. Although the claims at issue are not identical, they are not patentably distinct from each other.
Claims 1, 7 and 13 in `982 are directed to a system and a method of altering a genome of a cell and method of treating a hemoglobinopathy that each disclose a gRNA. Claims 2-6 that depend from claim 1, claims 8-11 that depend from claim 7 and claims 14-17 that depend from claim 13 each identify that the target for the gRNA in claims 1, 7 and 13 is BCL11A gene, DHS in intron 2 that +58TSS.
Therefore, in teaching a system and methods that uses a gRNA that is a nucleic acid and targets intron 2 in BCL11A gene at DHS sites, claims 11-11, 13-17in `982 render obvious the instantly claimed gRNA of claims 190, 192, 196, 198, 210-217.
Conclusion
No claim is allowed.
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/MATASHA DHAR/Examiner, Art Unit 1632