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 .
Response to Amendment
The amendment filed 10/22/2025, amending claim(s) 19, 29, and 30 and cancelling claim(s) 31 and 32 is acknowledged. Claims 19-21, 29, and 30 are pending and under examination. Applicant’s amendments to the claims have overcome each and every claim objection, 112(b) rejection, and 102 rejection previously set forth in the Non-Final Office Action mailed 04/22/2025.
Priority
The claims of the instant case are entitled to the priority date of provisional application 62872514, filed 07/10/2019.
Claim Rejections - 35 USC § 101 – New, necessitated by amendment
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 19, 29, and 30 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more. The claim(s) recite(s) “a first RNA molecule comprising a guide sequence portion consisting of the nucleic acid sequence any one of SEQ ID NOs: 1-144” (claim 19) and “a first RNA molecule comprising a guide sequence portion consisting of the nucleic acid sequence of any one of SEQ ID NOs: 16, 81, 103, 112, and 131” (claim 29). According to the 2019 Revised Patent Subject Matter Eligibility Guidelines (2019PEG), the claim is first analyzed to determine if it is directed to one of the acceptable statutory categories of invention (i.e., process, machine, manufacture, or composition of matter). Claims 19, 29, and 30 are drawn to a product comprising an RNA molecule, and products are compositions of matter. Thus, claims 19, 29, and 30 meet the requirements for step 1 analysis.
Second, the claim is assessed to determine if it is directed to a judicial exception under step 2A. Under 2019PEG, “directed to” is determined via a two-prong inquiry: (1) Does the claim recite a law of nature, a product of nature, a natural phenomenon, or an abstract idea; and (2) Does the claim recite additional element(s) that integrate the judicial exception into a practical application. The phrase, “integration of a practical application”, requires the presence
of an additional claim element(s) or a combination thereof to apply, rely on, or use the judicial
exception in a manner that imposes a meaningful limitation on the judicial exception, such that
the claim does not monopolize the judicial exception (See MPEP § 2106.05 for examples of
integration of practical application).
Regarding the first prong (1), claims 19, 29, and 30 are directed to an RNA molecule comprising a guide sequence portion consisting of any one of SEQ ID NOs: 1-144 (SEQ ID NO: 16 previously elected for examination). The broadest reasonable interpretation “an RNA molecule comprising a guide sequence portion consisting of SEQ ID NO: 16” includes a naturally occurring RNA sequence.
[0008] of the specification discloses “The present disclosure provides a method for utilizing at least one naturally occurring nucleotide difference or polymorphism (e.g., single nucleotide polymorphism (SNP)) for distinguishing/discriminating between two alleles of a gene”. Additionally, [0035] discloses “The guide sequence portion may be part of an RNA molecule that can form a complex with a CRISPR nuclease with the guide sequence portion serving as the DNA targeting portion of the CRISPR complex” (i.e., maybe part of is synonymous with not required). Therefore, the claims are directed to a seed sequence present in any RNA molecule. Further, Li teaches the single nucleotide polymorphisms (SNPs) being present in the RPE65 mRNA (Abstract).
Therefore, the claims are drawn to a natural phenomenon and the first prong of the inquiry demonstrates that claims 19, 29, and 30 are directed to a judicial exception.
Regarding the second prong (2), claims 19, 29, and 30 recite the additional element of “a guide sequence portion”. This recitation implies an intended use of the RNA molecule. As discussed above (e.g., [0008], Li), the broadest reasonable interpretation of the claimed genus of RNA molecules is broader in scope that gRNAs or sgRNAs and reasonably encompasses mRNAs. [0035] discloses the phrase "guide sequence portion" encompasses RNAs that are not required to bind to Cas nucleases. The additional element does not limit the structure or function of the RNA molecule and is solely descriptive of the intended use of the claimed RNA molecule. As such, no practical application is recited and therefore there is no integration into a practical application. Thus, claims 19, 29, and 30 meet the requirement of step 2A as being directed to a judicial exception.
Third, if a judicial exception is present in the claim, it is further assessed to determine if
the claims recite any additional elements or steps that are sufficient to ensure that the claim as
a whole amounts to significantly more than the judicial exception. As discussed above, the
additional element recited in the claims is an intended use that does not further limit the natural phenomenon judicial exception. In addition, the intended use does not impart any particular structural or functional limitation that further limits the generic nature of the natural phenomenon of the RNA molecule. Under the holding of Myriad, an isolated but otherwise unchanged nucleic acid was not patent eligible subject matter because it was not different enough from what exists in nature to avoid improperly tying up the future use and study of naturally occurring nucleic acid. The RNA molecule of the claims is analogous to the isolated nucleic acid in Myriad. The claimed RNA molecule can be interpreted as being an isolated RNA molecule that is otherwise unchanged. Thus, the isolated RNA molecule is not patent eligible subject matter because it is not different enough from RNA molecules that exist in nature to avoid improperly tying up the future use and study of the naturally occurring molecules and nucleases. As such, the additional element does not impart any structural or functional elements that markedly transform or distinguish the judicial exception from its natural counterpart, as exemplified by the specification and Li. Thus, claims 19, 29, and 30 do not meet the requirement for step 2B of the analysis.
In conclusion, claims 19, 29, and 30 do not meet all the requirements of the 2019PEG subject matter patentability. Therefore, the claims are deemed patent ineligible. The examiner notes it would be remedial to amend the claims to recite a "single guide RNA molecule", per [0123], instead of “RNA molecule comprising a guide sequence portion”.
Claim Rejections - 35 USC § 112(b) – New, necessitated by amendment
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 19-21, 29 and 30 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 19, 29, and 30 recite the phrase “comprising a guide sequence portion consisting of the nucleic acid sequence…”.
The recitation of “comprising” and “consisting of” are contradictory. The term "comprising" is open-ended and allows for additional, unrecited elements in the claims. MPEP 2111.03 specifically sets forth that the transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004). The term “consisting of” excludes any element, step, or ingredient not specified in the claim (see MPEP 2111.03).
Additionally, claim 30 recites “consists of the sequence set forth in SEQ ID NO: 16”. It is unclear to which sequence “set forth in SEQ ID NO: 16” is referring to. As discussed in the previous office action mailed 4/22/2025, the phrase “the sequence set forth in” renders the claims indefinite because the reference SEQ ID NO is composed of a plurality of amino acid subsequences or nucleotide subsequences, respectively, and it is unclear to which subsequence “set forth in” the reference SEQ ID NO Applicant refers. The preposition “in”, per “set forth in”, does not have the same meaning as the preposition “of”. For example, “in” indicates a location or position within a limit or reference, e.g. a fragment or some portion of the referenced SEQ ID NO. The preposition “of” indicates possession of the reference, characteristic, or trait, that is to say, the entirety of the referenced SEQ ID NO. To the extent that Applicant is referring to the entirety of the referenced SEQ ID NO, then replacing the phrase “the sequence set forth in” with the phrase “the sequence of SEQ ID NO:” would render the rejection moot.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, the claims recite the broad recitation “comprising”, and the claim also recites “consisting of” which is the narrower statement of the range/limitation. Additionally, claim 30 recites the broad recitation “set forth in SEQ ID NO: 16”, and the claim also recites “consists of the sequence” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
For examination purposes, the claims are interpreted to require the presence of SEQ ID NO: 16, but allows for additional nucleotides 5’ or 3’ to SEQ ID NO: 16, supported by [0084] of the specification which recites “In embodiments of the present invention, the RNA molecule may be 17 up to 300 nucleotides in length”.
It would be remedial to amend the claims to recite “a first single guide RNA (sgRNA) molecule consisting of the nucleic acid sequence of SEQ ID NO…”.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
Claim Rejections - 35 USC § 112(d) – New, necessitated by amendment
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 30 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.
Claim 29, of which claim 30 depends upon, recites “a first RNA molecule comprising a guide sequence portion consisting of the nucleic acid sequence of any one of SEQ ID NOs…”. Claim 30 recites “wherein the guide sequence portion consists of the sequence set forth in SEQ ID NO: 16”. Claim 30 is broader in scope than claim 29 because as written, it does not require all of SEQ ID NO: 16 (see 112(b) rejection above), while claim 29 does.
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 Rejections - 35 USC § 103 – New, necessitated by amendment
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 19-21, 29, and 30 is/are rejected under 35 U.S.C. 103 as obvious over Li (Li, Yan, et al. "Aberrant RNA splicing is the major pathogenic effect in a knock‐in mouse model of the dominantly inherited c. 1430A> G human RPE65 mutation." Human mutation 40.4 (2019): 426-443.; NPL #2 of IDS filed 02/20/2024) in further view of Fu (Fu, Yanfang, et al. "Improving CRISPR-Cas nuclease specificity using truncated guide RNAs." Nature biotechnology 32.3 (2014): 279-284.).
As discussed in the 112(b) rejection above, due to the recitation of both “comprising” and “consisting of” in the claims, the claims are interpreted to require the presence of SEQ ID NO: 16, but allows for additional nucleotides 5’ or 3’ to SEQ ID NO: 16 to be present. The broadest reasonable interpretation, as discussed in the 101 rejection above, encompasses any RNA molecule that comprises SEQ ID NO: 16, and the recitation of “guide sequence portion” is interpreted to be an intended use of the claimed RNA molecule and does not further limit its structure or function.
Regarding claims 19, 29 and 30, Li teaches a RNA molecule comprising a guide sequence portion having 17-25 contiguous nucleotides containing nucleotides in the sequence set forth in any one of SEQ ID NO: 16 (sequence of gRNA_c.1430 in Supp. Table S1) (upper line instant SEQ ID NO: 16, lower line gRNA sequence disclosed by Li):
Query Match 95.0%; Score 19; DB 1; Length 20;
Best Local Similarity 73.7%;
Matches 14; Conservative 5; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CAUCUUCUUCCAAGGCACC 19
||:|::|::||||||||||
Db 2 CATCTTCTTCCAAGGCACC 20
The sequence taught by Li differs from instant SEQ ID NO: 16 in it includes 1 additional nucleotide 5’ to instant SEQ ID NO: 16, and does not include the last nucleotide present at the 3’ end of instant SEQ ID NO: 16.
Fu teaches that truncated gRNAs, with shorter regions of target complementarity
<20 nucleotides in length, can decrease undesired mutagenesis at some off-target sites by 5,000-fold or more without sacrificing on-target genome editing efficiencies. In addition, use of truncated gRNAs can further reduce off-target effects induced by pairs of Cas9 variants that nick DNA (paired nickases) (Abstract). Fu notes that the tru-gRNAs generally function efficiently at the intended target site and have improved specificities in a gene of interest (pg. 283, col 2, para 2; Fig. 2).
It would have been obvious to one of ordinary skill before the effective filing date of the current invention to apply the knowledge that shorter regions of target complementarity in gRNAs can decrease undesired mutagenesis without sacrificing on-target genome editing efficiencies (e.g., a gRNA sequence that is 1 nucleotide shorter would not result in a failure of on-target genome editing). One would have a reasonable degree for success because Fu teaches successfully editing a gene of interest with a functional Cas nuclease and truncated sgRNA. One would be motivated to apply the teachings of Fu to the RNA molecule by Li in order to minimize the off-target effects of individual Cas9 nucleases, paired Cas9 nickases and, potentially, dCas9 fusion proteins in human cells (pg. 284, col 1, para 2).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
Further, the instant application fails to disclose an element of criticality for instant SEQ ID NO: 16, as opposed to the sequence as taught by Li (i.e., why/how does the 1 nucleotide at the 3’ end of SEQ ID NO: 16 that is not present in Li’s sequence result in a structural/functional difference compared to Li and the prior teachings in the art of generating truncated gRNA seed sequences by removing 1, 2, 3… nucleotides).
The "mere existence of differences between the prior art and an invention does not establish the invention's nonobviousness." Dann v. Johnston, 425 U.S. 219, 230, 189 USPQ 257, 261 (1976). The gap between the prior art and the claimed invention may not be "so great as to render the [claim] nonobvious to one reasonably skilled in the art."
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
Regarding claim 20, Li teaches a composition comprising the first RNA molecule of claim 19 and at least one CRISPR nuclease (e.g., Cas9) (Abstract; pg. 428, “2.3 Generation of Rpe65 c.1430A>G KI mice).
Regarding claim 21, Li teaches the composition of claim 20, further comprising a second RNA molecule comprising a guide sequence portion having 17-25 contiguous nucleotides, wherein the second RNA molecule targets a RPE65 allele, and wherein the guide sequence portion of the second RNA molecule is a different sequence from the sequence of the guide sequence portion of the first RNA molecule (i.e., Li references multiple gRNAs being designed and synthesized; wild-type (WT), knock-in (KI)/mutant alleles) (pg. 428, “2.3 Generation of Rpe65 c.1430A>G KI mice).
Response to Arguments
Applicant's arguments filed 10/22/2025 have been fully considered but they are not persuasive. The Applicant argues that in light of amending the claims to recite “a first RNA molecule comprising a guide sequence portion consisting of the nucleic acid sequence any one of SEQ ID NOs: 1-144” instead of “a first RNA molecule comprising a guide sequence portion having 17-25 contiguous nucleotides containing nucleotides in the nucleic acid sequence set forth in any one of SEQ ID NOs: 1-144”, Li no longer anticipates instant SEQ ID NO: 16. As discussed in the rejections above, the only differences between instant SEQ ID NO: 16 and the sequence taught by Li and the inclusion of an extra nucleotide at the 5’ end of Li’s sequence, and the inclusion of an extra nucleotide at the 3’ of instant SEQ ID NO: 16 not found in the sequence taught by Li. The instant application fails to provide an element of criticality for SEQ ID NO: 16 versus the sequence taught by Li. Additionally, the use of “comprising” in the claim language permits extra nucleotides to be present at the 5’ and/or 3’ ends of the sequence. Therefore, the arguments are not found to be persuasive and the teachings of Li still read upon the claimed invention.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALLISON M JOHNSON whose telephone number is (703)756-1396. The examiner can normally be reached Monday-Friday 9am-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, Tracy Vivlemore can be reached on (571) 272-2914. 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.
/ALLISON MARIE JOHNSON/Examiner, Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638