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 .
Claim Status
Claims 1-17 and 22-24 are pending and examined on the merits.
Claim Rejections - 35 USC § 112
Indefiniteness
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.
Claims 1-17 and 22-24 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 pre-AIA the applicant regards as the invention.
The claims all directly or indirectly recite dCas9. Claim 10 is drawn to the fusion protein of claim 1, wherein the dCas9 protein comprises at least one domain selected from the group consisting of: a Rec1 domain, a bridge helix domain, and a protospacer adjacent motif interacting domain. These three domains are defining domains that are present in any Cas9 protein. The presence of this claim indicates that Applicant intends to expand the definition of Cas9/dCas9 behind the normal art accepted definition, but fails to make clear the metes and bounds of the new meaning of Cas9/dCas9 in the specification. While Applicant is entitled to be their own lexicographer, when the intend to redefine a term to have meaning other than the art-accepted meaning, a new definite definition must be provided. As such, all claims are rejected as indefinite. The Examiner acknowledges that claims 12 and 15 recite an option to structurally limit the dCas9 as having a specified level of identity to an amino acid sequence or a polynucleotide encoding the dCas9, but no claim requires structural limitations on dCas9.
Claims 17 and 23 recite, “wherein the one or more gRNAs comprises a sequence having sufficient complementarity with a target polynucleotide sequence within the gen, and/or wherein the one or more gRNAs are capable of hybridizing with the target polynucleotide sequence.” Both of these limitations are necessary features of gRNAs. They target a site by hybridizing to a target site based on complementarity, so it is unclear how these could be considered alternatives, based on the recitation of “and/or.” Further, if the gRNAs are not able to target a site by hybridizing to a target site based on complementarity, it is unclear how the method claims 16 works, or how the viral vector of claim 22 is useful. Thus, the intention of claims 17 and 23 are intended to further limit their parent claims is also unclear.
Claim 22 recites the limitation "the polynucleotide according to claim 1." There is insufficient antecedent basis for this limitation in the claim. Claim 1 is drawn to a fusion protein not a polynucleotide.
Failure to Further Limit
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.
Claims 13 and 15 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 13 is drawn to the fusion protein of claim 1, wherein the fusion protein comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 13 or an amino acid sequence having one, two, three, four, five or more amino acid substitutions, insertions, or deletions relative to SEQ ID NO:13. The first part of the wherein clause includes SEQ ID NO: 13 and the second part of the wherein clause is claiming every amino acid sequence other than SEQ ID NO: 13 as every sequence can be made via the recitation of “having one, two, three, four, five or more amino acid substitutions, insertions, or deletions relative to SEQ ID NO:13.” Accordingly, claim 13 fails to further limit claim 1.
Claim 15 has the same issue by virtue of the similar recitation regarding SEQ ID NO: 7 and the use of “and/or” between the different items in the claim.
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.
Lack of Written Description
The following is a quotation 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.
Claims 1-17 and 22-24 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims all require a dCAS9 protein or a polynucleotide encoding a dCAS9 protein. As discussed in the indefiniteness rejection above, a person of ordinary skill in the art would not have been able to tell what is intended to be encompassed with the scope of a “dCAS9” protein given the instant claims and specification.
Given the inability of a person of ordinary skill to even understand the scope of “dCAS9,” they could not possibly recognize that Applicant was in possession of the claimed genus at the time of filing.
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) 1-4, 9-17, and 22-24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yeo et al 2018 (Nature Methods 15: p. 611-616, Supplementary Information attached to NPL in folder), and further in view of Taipale et al (US 20230287391 A1) which has priority back to 14 August 2020.
Yeo et al teach making bipartite repressor domain fusions with dCAS9 in an effort to build a better repressor fusion protein that may be targeted through the use of a guide RNA. Using a fluorescent screening marker, they found that the KRAB-MeCP2-dCAS9 fusion performed better than most other bipartite fusions (Supplementary Figure 2). Using several of the better-performing bipartite fusions found that KRAB-MeCP2-dCAS9 fusion performed best (Supplementary Figures 3, 5-7). Supplementary Table 1 show the KRAB-MeCP2-dCAS9 coding sequences. The encoded protein is as follows: dCAS9 - SV40 NLS – linker – KOX1 KRAB – linker – MeCP2. The dCAS9 comprises the well-known mutations recited in claim 11 and is over 99% identical to SEQ ID NO: 16. The coding sequences were used to make stable human cell culture lines. That were then infected with lentiviral vectors comprising sequences encoding sgRNAs to direct the fusion repressor to chosen target sites (Methods, p. 616-617).
Yeo et al do not teach the Zim3 KRAB domain.
Taipale et al teach 57 different KRAB domains for repressor activity when fused to a dCAS9 polypeptide. They found that the Zim3 KRAB domain outperformed other KRAB domains (paragraph 7, Figures 2-3, 5-6). They also used the same dCAS9 as instantly claimed. They teach that the lentiviral vector can be used to deliver sequences encoding repressor fusion proteins (claim 12). They teach that the repressor can be labeled with tags including the fluorescent tags GFP and mCHERRY (paragraph 56).
At the time of filing, it would have been prima facie obvious for a person of ordinary skill in the art to substitute the Zim3 KRAB domain of Taipale et al for the KOX1 KRAB domain used by Yeo et al as Taipale et al demonstrated that the Zim3 KRAB domain leads to better repression than the KOX1 KRAB domain. In making this substitution a person of ordinary skill would arrive at the following fusion protein dCAS9 - SV40 NLS – linker – Zim3 KRAB – linker – MeCP2. Absent any evidence to the contrary, this appears to an obvious variant of the fusion protein of claim 4 which has the repressor domains N-terminal to the NLS-dCAS9. Being that they comprise all the necessary element, a person of ordinary skill in the art would have expected that they would perform similarly. Also note that claim 4 have no functional recitations as to the effectiveness of the repressor. Accordingly, claims 1-4, 9-17, and 22-24 are rejected as being obvious over Yeo et al further in view of Taipale et al.
Claim(s) 5-6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yeo et al 2018 (Nature Methods 15: p. 611-616) and Taipale et al (US 20230287391 A1, which has priority back to 14 August 2020) as applied to claims 1-4, 9-17, and 22-24 above, and further in view of Segal et al (US 20190233805 A1).
Yeo et al and Taipale et al collectively teach all the limitations of claim 1.
Yeo et al and Taipale et al collectively do not teach a repressor fusion protein comprising the FOG1 pressor domain.
Segal et al teach FOG1-dCAS fusion proteins that can be directly to repress gene expression at a given locus by directing heterochromatin formation to occur at the given locus.
At the time of filing, it would have been prima facie obvious for a person of ordinary skill in the art to substitute the FOG1 repressor domain of Segal et al for either the KRAB domain or the MeCP2 domain in the bipartite repressor dCAS9 fusion protein of Yeo et al in view of Taipale et al. In making these substitutions, a person of ordinary skill in the art would have arrived at the fusion proteins claimed in claims 5-6. A person of ordinary skill in the art would have had a reasonable expectation of success in practicing the invention as only long-practiced molecular cloning methods would have been required. Note that there is no functional requirement for the proteins recited in the claims.
Conclusion
No claims are allowed.
Claims 7-8 are not currently rejected over the prior art as the only exemplification of a tripartite repressor fused to a dCas9 was in Supplementary Figures 4-5 of Yeo et al which found that the tripartite repressor fusions performed worse than some of the bipartite repressor fusions. Absent other working examples in the prior art to the contrary, this constitutes a teaching away from making a tripartite repressor fusion. If Applicant is aware of such prior art, they are urged to make it of record and explicitly point it out, so that the Examiner may thoroughly consider it in regard to the patentability of the examined claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATTHEW R KEOGH whose telephone number is (571)272-2960. The examiner can normally be reached M-Th 7-4:30, half day on Fridays.
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, Amjad Abraham can be reached on 571-270-7058. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MATTHEW R KEOGH/Primary Examiner, Art Unit 1663
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