Notice of Pre-AIA or AIA Status
Claims 1-5, 7, 10, 12, 16, 18-19, 23-24, 26, 29-32, 34, and 37 are pending and examined herein.
Claims 6, 8-9, 11, 13-15, 17, 20-22, 25, 27-28, 33, and 35-36 are canceled.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Objections
Claim 10 is objected to because of the following informalities: it recites "a second label" when there is no first label recited in this claim. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1-5, 7, 10, 12, 16, 18-19, 23-24, 26, 29-32, 34, and 37 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.
The terms “template-conserved” and “template-randomized” in claims 1, 3, 18, 24, 29-30, and 32 are relative terms which renders the claim indefinite. The terms “template-conserved” and “template-randomized” are not defined by the claim, the specification does not provide a definition, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what the “template” is referring to, and therefore it is unclear what would qualify a nucleic acid region as conserved or randomized relative to the template. For the purposes of examination, “template-conserved” and “template-randomized” will be interpreted to mean “conserved” and “randomized”, respectively. Therefore, candidate guide nucleic acids are limited to having a conserved target complementary region and a randomized scaffold. This rejection may be overcome by providing a defined “template” for comparison in the claim. Other solutions are possible. Claims 2, 4-5, 7, 10, 12, 16, 19, 23, 26, 31, 34, and 37 are similarly rejected as they are each dependent on one of the above claims.
Claim 10 recites the limitation "the Cas9 protein" in line 1. There is insufficient antecedent basis for this limitation in the claim. This rejection may be rectified by changing the limitation to recite “the Cas protein”, as to have proper antecedent basis in claim 1. This is the interpretation that will be used for examination purposes. Other solutions are possible.
Claim 10 also recites the limitation “the cleaved double-stranded target nucleic acid” in line 4. There is insufficient antecedent basis for this limitation in the claim. This rejection may be rectified by changing claim 10 to be dependent on claim 3, which contains antecedent basis. The claim will be interpreted as though it is dependent on claim 3 for the purposes of examination. Other solutions are possible.
Claim 12 also recites the limitation of a guide nucleic acid having “miRNA modulated activity”. This term renders the claim indefinite because it is not clear what “miRNA modulated activity” entails, nor is it defined in the specification. It is unclear because it does not specify what is being modulated, what “modulation” entails, nor what the expected result of the “modulation” would be. Based on the specification, this limitation will be interpreted to mean that the guide nucleic acid can be bound by a miRNA, which then results in an increase or decrease in either the binding of the guide nucleic acid to Cas or the cleavage activity of the Cas-guide nucleic acid complex. To overcome this rejection, the limitation can be re-written to explicitly define what is being modulated and what the expected outcome(s) would entail. Other solutions are possible.
Claim 16 recites the limitation "the template" in line 3. There is insufficient antecedent basis for this limitation in the claim. Additionally, as “the template” is indefinite, this renders the entirety of the required limitations of claim 16 indefinite, as it is unclear what the candidate guide nucleic acids are being compared to for having increased cleavage activity.
Claims 18, 31, and 37 currently make reference to Tables 1, 2, and 3 in the specification. However, as per MPEP § 2173.05(s), “[w]here 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).” In the present case, Tables 1, 2, and 3 appear to consist of SEQ ID NOs, such that one possibility to overcome the rejection would be to amend the claims to replace “Table 1, Table 2, or Table 3” with the appropriate SEQ ID NOs. Other solutions are also possible.
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.
Claim 7 is 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. All recited limitations of claim 7 are previously recited in claim 1, upon which claim 7 is dependent. Claim 7 attempts to further limit the method of claim 1 by reciting that the method comprises (i) contacting Cas with candidate guide nucleic acids and the target nucleic acid, which is previously recited in 1a. Claim 7 also recites (ii) partitioning candidate guide nucleic acids with increased binding, which is previously recited in 1b. Finally, claim 7 recites (iii) amplifying the candidate guide nucleic acids with increased binding, which is recited in claim 1c. As all limitations recited in claim 7 are present in claim 1, upon which it is dependent, claim 7 fails to further limit the method as described in claim 1. 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.
Claim Interpretation
As discussed previously, the terms “template-conserved” and “template-randomized” are recited in claims 1, 3, 18, 24, 29-30, and 32, and are being interpreted as “conserved” and “randomized”, respectively, for examination. In the claims where more than one guide nucleic acid is claimed (claims 1, 3, 24, and 29-30), the broadest reasonable interpretation of these limitations is that the target complementary regions are constant throughout the guide nucleic acids, while the scaffold region is not required to be. However, in the claims where a single guide nucleic acid is claimed (claims 18 and 32), whether or not a region is “conserved” or “randomized” does not constitute a structural limitation as, theoretically, any guide nucleic acid sequence could be obtained from an undefined template.
Claim 12 recites a clause of optional limitations, followed by an additional “and wherein” limitation. Based on the punctuation, this final “and wherein” limitation will be interpreted to be part of the optional limitation clause. This means that everything following “and optionally” in claim 12 is considered to be an optional limitation.
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.
Avila et al.
Claims 1-3 and 7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Avila et al. (US PGPub 2021/0017516).
Regarding claims 1 and 7, Avila describes a method for generating guide nucleic acids that bind a Cas protein (p. 5-6, ¶[0037]) comprising:
contacting the Cas protein with candidate guide nucleic acids and a target nucleic acid (p. 66, ¶[0094]), the candidate guide nucleic acid having a conserved target complementary region (p. 9, ¶[0057]) and a randomized scaffold (p. 66, ¶[0099]), wherein the complementary region can hybridize to dsDNA proximate to PAM (p. 66, ¶[0095]) and the scaffold comprises a degenerate 5’ portion and an invariant 3’ end (p. 10, ¶[0062]; Fig. 4E);
partitioning candidate guide nucleic acids having increased binding affinity to the Cas protein from those that do not (p. 66, ¶[0101]); and
amplifying the candidate guide nucleic acids having increased binding affinity (p. 66-67, ¶[0102]).
Regarding claim 2, Avila further discloses a catalytically dead Cas (p. 66, ¶[0094]).
Regarding claim 3, Avila discloses a method for generating guide nucleic acids that allow cleavage of a double-stranded nucleic acid target when in complex with a Cas protein (p. 6: “Processing-Screening”) comprising:
contacting the Cas protein (p. 6, ¶[0039], lines 16-19) with candidate guide nucleic acids (p. 6, ¶[0039], lines 37-38) and a target nucleic acid (p. 6, ¶[0039], lines 10-13), the candidate guide nucleic acid having a conserved target complementary region (p. 9, ¶[0057]) and a randomized scaffold (Fig. 4A), wherein the complementary region can hybridize to dsDNA proximate to PAM (p. 9, ¶[0057]) and the scaffold comprises a degenerate 5’ portion and an invariant 3’ end (p. 10, ¶[0062]; Fig. 4E);
partitioning candidate guide nucleic acids having increased binding affinity to the Cas protein from those that do not (p. 7, ¶[0042], lines 7-10); and
amplifying the candidate guide nucleic acids having increased Cas complex cleavage activity (p. 7, ¶[0042]).
Jayaram et al.
Claims 18-19 and 23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jayaram et al. (US PGPub 2018/0135109).
Regarding claim 18, Jayaram discloses a guide nucleic acid comprising a complementary region and a scaffold, wherein the complementary region can hybridize to a double-stranded nucleic acid target proximate to a PAM sequence and the scaffold region has binding affinity for a Cas protein, and the guide nucleic acid comprises an RNA according to SEQ ID NO. 547 (Jayaram SEQ ID NO: 507).
Regarding claim 19, Jayaram further discloses that the guide nucleic acid comprises a functional site (“termination domain” – p. 16, ¶[0192]; Fig. 7).
Regarding claim 23, Jayaram further discloses that the guide nucleic acid binds to a Cas9 endonuclease (p. 44, ¶[0685-6]).
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.
Avila et al. and Loo
Claims 4 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Avila in view of Loo (Chapter 1, DNA Damage Detection In Situ, Ex Vivo, and In Vivo: Methods and Protocols, Methods in Molecular Biology, vol. 682).
Avila discloses all limitations of claim 3. However, Avila does not disclose use of a terminal deoxynucleotidyl transferase (TdT) polymerase, nor labeling the free PAM-distal non-target strand with a labeled nucleotide.
Loo discloses that TUNEL (TdT-mediated dUTP-biotin nick end labeling) is a commonly used procedure for labeling free 3’ ends of DNA (p. 4, lines 1-7). Loo also discloses that this method is suitable for the general detection of DNA damage, including DNA cleavage (p. 4, lines 15-17). This indicates that this method would serve the function of labeling free 3’ ends that result from Cas complex cleavage. As the TUNEL method is well-known in the art for labeling free 3’ ends of DNA resulting from DNA cleavage, it would have been obvious to one of ordinary skill in the art by the effective filing date to substitute the detection method of Avila with TUNEL as both methods serve the same function. Additionally, this substitution would result in the predictable method of using TdT to label the free PAM-distal non-target strand with a biotin-labeled nucleotide.
Avila et al. and Jayaram et al.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Avila et al. in view of Jayaram et al.
Avila discloses all limitations of claim 3, as described above. Avila further discloses that the Cas protein is an S. pyogenes Cas9 endonuclease (p. 8, ¶[0051]). However, Avila does not disclose that the target nucleic acid comprises a label.
Jayaram discloses a cleavage assay for screening guide nucleic acids where the target nucleic acid comprises a label (p. 33, ¶[0556]). This is a method well-known in the art for measuring cleavage of a target nucleic acid by a Cas protein, and can additionally be used to indicate cleavage of one or both strands of the target, as taught by Jayaram (p. 33, ¶[0556]). Therefore, one of ordinary skill in the art by the effective filing date, could have combined the method of Avila with the label of Jayaram, yielding the predictable result of the cleaved double-stranded target nucleic acid further comprising a label.
Avila et al. and Wang et al.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Avila et al. in view of Wang et al. (Nat. Cell Biol. (2019), 21:52-530).
Avila discloses all limitations of claim 1, as discussed above. However, Avila does not disclose that the amplified candidate guide nucleic acid has a miRNA domain.
Wang discloses a guide nucleic acid that has a miRNA domain (p. s22, “Design of an miRNA-inducible CRISPR-Cas9 platform; Fig. 1a). Additionally Wang teaches that this guide nucleic acid “achieve[s] cell-type-specific control of CRISPR–Cas9 systems for genome editing, precise base editing, epigenome modification and transcriptional regulation” and that it could be used for “targeted genome regulation to engineer specific cells for biology, therapeutic and synthetic biology applications” (p. s29, Discussion, col. 2). The range of applications taught by Wang demonstrates that a guide nucleic acid with a miRNA domain could be widely useful, providing motivation for the incorporation of a miRNA domain into putative guide nucleic acids. Therefore, it would have been obvious to one of ordinary skill in the art by the effective filing date, to use the method of Avila to identify guide nucleic acids containing miRNA domains, resulting in the predictable outcome of a method for generating a guide nucleic acid having miRNA modulated activity.
Jayaram et al. and Loo
Claims 24, 29-32, 34, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Jayaram et al. in view of Loo.
Regarding claim 24, Jayaram discloses a mixture comprised of more than one candidate guide nucleic acid (p. 9, ¶[0111]) that have common target complementary regions and distinct scaffolds (p. 10, ¶[0124]), wherein the target complementary region is configured to hybridize to a double-stranded DNA proximate to a PAM sequence and wherein the scaffold has binding affinity for a Cas protein (p. 9, ¶[0057]: gRNA). Jayaram does not disclose that the mixture comprises a polymerase nor a labeled nucleotide.
As discussed in regards to claims 4 and 5 above, Loo discloses the TUNEL method for detecting DNA cleavage. As Jayaram also discloses a method for screening guide nucleic acids for cleavage activity when in complex with Cas, the method of Loo renders the further limitations of a polymerase and labeled nucleotide obvious, per the reasoning discussed previously.
Claim 29 recites the limitation that the mixture of claim 24 was made by a method comprising steps enumerated therein. However, this type of claim is considered a ‘product-by-process’ claim, as described in MPEP § 2113. Additionally, the MPEP states that the patentability of product-by-process claims is limited to the structure of the product as required by the process steps. In the case of claim 29, the only additional limitation not included in claim 24 is that of 24c, which states that the mixture is “enriched for candidate guide nucleic acids having binding affinity for the Cas protein”. The structural limitation required by this is that the mixture must have candidate guide nucleic acids that have binding affinity for the Cas protein. As the guide nucleic acids of Jayaram are screened for Cas9 binding (p. 10, ¶[0123]), this indicates that the prior art meets this limitation.
Claim 30 recites the limitation that the mixture of claim 24 is for use in a method comprising steps enumerated therein. The recitation of “for use in the method comprising…” of the instant claim 30 is a recitation of intended use of the instant claimed 24 and a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. As the mixture of Jayaram and Loo is compatible with the method as described, claim 30 is rendered obvious by the disclosures of the prior art.
Regarding claim 31, Jayaram further discloses that one of the candidate guide nucleic acids comprises an RNA according to SEQ ID NO. 547 (Jayaram SEQ ID NO: 507).
Regarding claim 32, Jayaram discloses a Cas complex (p. 10, ¶[0119-20]) comprising a Cas protein (Cas9 molecule), a candidate guide nucleic acid with a target complementary region and a scaffold with binding affinity for the Cas protein (gRNA molecule), and a cleaved target nucleic acid (p. 33, ¶[0556]). Jayaram does not disclosed that the free single-stranded 3’ end is labeled. However, Loo discloses a labeled free single-stranded 3’ end as discussed previously, rendering obvious this limitation.
Regarding claim 34, Jayaram further discloses that the Cas protein is S. pyogenes Cas9 and that the cleaved target nucleic acid comprises a second label (p. 33, ¶[0556]). Additionally, Loo further discloses that the labeled 3’ end is biotinylated (p. 6, 3. Methods: “incorporation of biotinylated-dUTP onto the 3’ ends of fragmented DNA”).
Regarding claim 37, Jayaram further discloses that the candidate guide nucleic acid comprises an RNA according to SEQ ID NO. 547 (Jayaram SEQ ID NO: 507).
Allowable Subject Matter
Claim 26 is objected to as being dependent upon a rejected base claim, but would be free of the prior art if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Alexandra Olson whose telephone number is (571)272-7519. The examiner can normally be reached Monday-Friday 9-5pm.
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, Heather Calamita can be reached at (571) 272-2878. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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.
/ALEXANDRA OLSON/Examiner, Art Unit 1684
/JEREMY C FLINDERS/Primary Examiner, Art Unit 1684
Prosecution Insights