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 a gNA targeting sequence of SEQ ID NO:321 and of an NLS sequence of SEQ ID NO:167 in the reply filed on 10/02/2025 was acknowledged in the non-final action mailed 12/23/2025.
Claims Status
Claims 3-10, 12-27, 30-40, 42-46, 48-51, 53-64, 66-78, 80, 82-83, 85-92, 94, 96-111, 113-114, 116-146, 148-192 is/are cancelled. Claims 1-2, 11, 28-29, 41, 47, 52, 65, 79, 81, 84, 93, 95, 112, 115, 147, 193 is/are currently pending. Claims 1-2, 11, 28-29, 41, 46-47, 52, 65, 79, 81, 84, 93, 95, 112, 115, 147, 193 is/are under examination.
Claim Objections
Claim 52 is objected to because of the following informalities:
“is identical to” in line 5 (newly added language) is grammatically incorrect. The current phrasing is as follows (lines 3-5): “when any one of the PAM sequences TTC, ATC, GTC or CTC is located 1 nucleotide 5’ to the non-target strand sequence is identical to the targeting sequence of the gNA”. The phrasing that “is identical to” replaced in the current amended claims was “having identity with”, which was grammatically correct. In order to correct this phrasing, the examiner suggests replacing “is identical to” with “identical to”, such that this section of claim 52 now reads: “when any one of the PAM sequences TTC, ATC, GTC or CTC is located 1 nucleotide 5’ to the non-target strand sequence identical to the targeting sequence of the gNA”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
112(b):
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 11 and 147 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 term “about” in claims 11 and 147 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The term “about” indicates an acceptable amount of error or variance; however, this acceptable amount of error or variance is not standardized or commonly agreed upon in the art. Without a description of the bounds on the amount of error or variance indicated by the term “about”, the metes and bounds of limitations modified by the term “about” are left unclear. Thus, claims 11 and 147 are rendered indefinite. This is a new grounds of rejection.
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.
Written Description:
Claims 1-2, 11, 28-29, 41, 47, 52, 65, 79, 81, 84, 93, 95, 112, 115, 147, 193 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V, v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Eiees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641,1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F. 2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it”).
According to the MPEP § 2163, "The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutsch land GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.")."
Claims 1 and 79 recite CasX variant proteins comprising sequences at least 90% identical to SEQ ID NO:138. This creates an enormous genus of proteins.
Claims 1 and 79 recite gNAs comprising target sequences “complementary to a target nucleic acid sequence comprising a chromosome 9 open reading frame 72 (C9orf72) gene” (lines 7-8), creating an enormous genus of gNA targeting sequences (as a nucleic acid comprising a C9orf72 gene encompasses expression plasmids and the entirety of chromosome 9), whereas the disclosure only provides gNA sequences targeting a C9orf72 gene or associated expression control regions. Claim 11 recites a gNA comprising a sequence at least 65% identical to SEQ ID NOs:309-343, 363-2100, or 2295-21835, which does not sufficiently further describe the genus of targeting sequences of claim 1.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. In the instant case, the only species of variant CasX proteins described comprise SEQ ID NOs:72, 94, 113, 130-138, 141-144, 239, 277, or 280 (paragraph [0201]); the only species of gNA targeting sequences are SEQ ID NOs:309-343, 363-2100, and 2295-21835 (paragraph [0101]). While the genera encompass a large number of variant proteins and gNA sequences that have the same activity (RNA-guided DNA-targeting and cleaving activity of variant CasX proteins, CasX- and DNA-binding activity of variant gNA sequences) and the genera encompass large numbers of variants and molecules that have different structures, the specification does not describe the complete structures of representative numbers of species of the large genera of variant CasX proteins and variant gNA sequences.
Next, then, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics (i.e., other than amino acid or nucleotide sequence, or chemical modification), specific features and functional attributes that would distinguish different members of the claimed genera. In the instant case, the only other identifying characteristic of the variant CasX proteins is that they “exhibit at least one improved characteristic compared to the reference CasX protein” (paragraph [0172]), wherein the at least one improved characteristic can be, but is not limited to, “improved folding of the variant, improved binding affinity to the gNA, improved binding affinity to the target DNA, altered binding affinity to one or more PAM sequences, improved unwinding of the target DNA, increased activity, improved editing efficiency, improved editing specificity, increased activity of the nuclease, increased target strand loading for double strand cleavage, decreased target strand loading for single strand nicking, decreased off-target cleavage, improved binding of the non-target strand of DNA, improved protein stability, improved protein:gNA complex stability, improved protein solubility, improved protein:gNA complex solubility, improved protein yield, improved protein expression, and improved fusion characteristics” (paragraph [0175]). The only other identifying characteristic of the variant gNAs is that they “have one or more improved functions or characteristics, or add one or more new functions when the variant gNA is compared to a reference gRNA”, including, but not limited to, “improved stability; improved solubility; improved transcription of the gNA; improved resistance to nuclease activity; increased folding rate of the gNA; decreased side product formation during folding; increased productive folding; improved binding affinity to a CasX protein; improved binding affinity to a target DNA when complexed with a CasX protein; improved gene editing when complexed with a CasX protein; improved specificity of editing when complexed with a CasX protein; and improved ability to utilize a greater spectrum of one or more PAM sequences, including ATC, CTC, GTC, or TTC, in the editing of target DNA when complexed with a CasX protein” (paragraph [0111]). The specification also teaches that the gNA targeting sequence may target a portion of the C9orf72 gene or an associated regulatory sequence (paragraphs [0099]-[0100]). Such functional limitations cannot be identifying characteristics for the claimed diverse genera of molecules since by Applicant’s definition of variant CasX proteins and gNAs, all members of the claimed genera will have these characteristics. Further, no identifying characteristics of the modified CasX proteins and gNAs are disclosed.
The inventions of claims 2, 28-29, 41, 46-47, 52, 65, 81, 84, 93, 95, 112, 115, 147, 193 require the use of the inventions of claims 1, 11, and 79 and are likewise rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement.
Enablement:
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 95, 112, 115, 147, and 193 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not reasonably provide enablement for a method of modifying a C9orf72 gene in vivo, ex vivo, or in vitro by targeting a gNA to a sequence not comprised in a C9orf72 gene or C9orf72 gene expression control region, or for a method of treating a disease associated with C9orf72 by targeting a gNA to a sequence comprised in a C9orf72 gene or C9orf72 gene expression control region. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. This rejection is modified to include a new grounds of rejection (in vitro and ex vivo methods of modifying C9orf72 with gNA not targeting C9orf72 but another sequence within a sequence comprising C9orf72).
The breadth of the claims:
With respect to claim breadth, the standard under 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. As such, the broadest reasonable interpretation of the claimed methods is that they encompass methods of modifying a sequence comprising a C9orf72 gene sequence in a population of cells in vitro or in vivo, and of treating a disorder associated with C9orf72 (see claim 193), by administering a CasX-gNA system, wherein the gNA targets any sequence comprising a C9orf72 gene sequence, encompassing a gNA targeting any target sequence anywhere in human chromosome 9 or in any vector or construct comprising a C9orf72 gene sequence. A skilled artisan would not know how to use the method with a reasonable expectation of success based solely on what is disclosed in the specification.
The amount of direction provided by the inventor and the level of predictability in the art:
The specification teaches that the intended use of the claimed methods of modifying a C9orf72 gene in vivo is in a method of treating amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (paragraphs [0003]-[0006]). The art at the time of filing provided enabling guidance for expected therapeutic efficacy of Cas9-gRNA systems in the treatment of C9orf72-related ALS and FTD, wherein the gRNA targets the promoter region controlling expression of C9orf72 (Krishnan, 2020), or wherein the gRNAs target two sequences within the C9orf72 gene and flanking the GC-rich expansion region (Pribadi, 2016). However, the prior art did not provide enabling guidance for methods of treating C9orf72-related diseases ALS and FTD using gRNA targeting any other sequence within the C9orf72 gene sequence or a C9orf72 expression control region, or any sequence not in the C9orf72 gene or expression control region. The specification as filed does not provide guidance that overcomes this unpredictability within the art.
The existence of working examples:
What is enabled by the working examples is narrow in comparison to the breadth of the claims: The specification discloses working examples in vitro wherein the CasX-gNA systems are shown to be capable of targeting and cleaving a C9orf72 gene sequence (paragraphs [0533]-[0548]). The specification provides prophetic examples of methods of treating animal models of C9orf72-related neurodegeneration; however, the disclosure teaches gNA targeting the promoter region, Exon 1, and Intron 1, including HRE, of C9orf72 (see Fig. 22).
The quantity of experimentation needed to make or use the invention:
The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004). The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution. Given that the nature of the invention encompasses in vivo treatment of any C9orf72-related disease using a gNA targeting any sequence anywhere within any nucleic acid comprising a C9orf72 gene (including all of human chromosome 9), a person having ordinary skill in the art would have to perform multiple further experiments, in human clinical trials or in animal models that are predictive of treatment, using a representative number of gNAs targeting a representative number of sequences comprised in any nucleic acid comprising a C9orf72 gene, in order to demonstrate the invention could be used with a reasonable expectation of success. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to use the method with a reasonable expectation of successfully treating any CNS disorder or neurodegenerative disease. Therefore, Claims 95, 112, 115, and 193 are rejected under 35 U.S.C. 112, first paragraph, for failing to meet the enablement requirement.
Response to Arguments
Applicant's arguments filed 04/14/2026 have been fully considered but they are not fully persuasive.
Regarding the written description rejection:
Applicant argues on page 13 of Remarks that the “Specification describes numerous variants at the 90%+ sequence identity level (e.g., SEQ ID NOs:130-138, 141-144, 239, 277 and 280), and this threshold represents a range within which structure-function relationships remain predictable for CasX variant proteins.” However, the applicant does not provide evidence that this threshold does represent a range within which structure-function relationships remain predictable for CasX variant proteins. As CasX varies substantially in sequence from other CRISPR endonucleases, such as Cas9, evidence of CasX structure-function understanding which would lend such predictability to variant CasX proteins must be provided in the disclosure or from the prior art and made of record.
Applicant further asserts that the amendments to claim 11 overcome the written description rejection regarding claim 11. However, claim 11 recites a minimum percent sequence identity of the gNA targeting sequence of 65% and of the gNA scaffold sequence of 70%. Such a degree of variance in the targeting and scaffolding sequences introduce unpredictability in the ability of the gNA to target the desired sequence (due to mismatches) or to bind to the CasX protein. It is known in the art that Cas9 systems are able to tolerate a limited number of mismatches between gRNA targeting sequences and targeted sequences (up to 2 mismatches, with positioning of the mismatches determining the tolerance of the system to the mismatches, see Anderson, 2015).
Regarding both CasX variants and gNA targeting and scaffold sequence variants, the disclosure has not described which sequence elements may be altered or must be conserved, and the applicants have not provided evidence that 90%+ sequence identity of CasX variants, 65%+ sequence identity of gNA targeting sequences, and 70%+ sequence identity of gNA scaffold sequences maintain predictability of structure and function of CasX and gNA variants.
Regarding the enablement rejection:
Applicant argues that the Examiner’s interpretation of gNAs “complementary to a target nucleic acid sequence comprising a C9orf72 gene” is unreasonably broad, and that the broadest reasonable interpretation is that the target comprises the C9orf72 gene, not any arbitrary sequence on chromosome 9. However, a chromosome comprises a nucleic acid sequence which comprises a C9orf72 gene, in addition to a multitude of other genes and non-coding sequences. If a target sequence is one which comprises within the specific sequences complementary to the gNA targeting sequences, then the entirety of chromosome 9, or of any sequence including an expression plasmid, which comprises C9orf72 gene is encompassed by a target sequence. If a target sequence is intended to encompass only the sequences complementary to a gNA targeting sequence (i.e., the sequences identical in length and complementary in sequence to the gNA targeting sequence), then it would not be reasonable to state that the target sequence comprises a C9orf72 gene, as the C9orf72 gene is longer than any gNA targeting sequence and thus cannot reasonably be considered to be comprised within a sequence complementary to and equal in length to a gNA targeting sequence. Applicant asserts that “one of skill in the art would understand the claims to be limited to sequences within or directly associated with the C9orf72 locus” (page 15). While this is the scope that is supported by the disclosure, the particular phrasing of claim 1 is broader than the scope supported by the disclosure. The examiner suggests that “complementary to a target nucleic acid sequence comprising a chromosome 9 open reading frame 72 (C9orf72) gene” be amended to one of the following, or to a similar phrasing:
“complementary to a target nucleic acid sequence comprised in a chromosome 9 open reading frame 72 (C9orf72) gene or in an expression control region of a C9orf72 gene”, or “complementary to a target nucleic acid sequence comprised within” a SEQ ID NO corresponding to the desired target sequence(s) (e.g., a C9orf72 gene sequence and desired associated sequences).
Applicant argues that the over 21,000 specific targeting sequences “target various positions within and around the C9orf72 gene” and that the “in vitro working examples demonstrate that the CasX-gNA systems effectively cleave C9orf72 sequences using these guides” (page 15). Applicant argues that by the effective filing date, “AAV-mediated delivery of CRISPR systems to the central nervous system (CNS) had been demonstrated in multiple publications and clinical contexts”, and that an artisan would reasonably expect success in the claimed in vivo methods (page 15). As discussed above, the breadth of the claimed target sequences is not fully supported by the disclosure and only gNAs targeting a C9orf72 gene sequence or directly associated sequences described in the disclosure would be so enabled. Examiner concedes that in vivo administration of CRISPR systems was established in the art; however, the treatment of C9orf72-associated diseases using CRISPR systems was not well-established in the art, and thus the disclosure and prior art do not support enablement for instant claim 193. If the targeting sequences of claim 1 are amended to be limited to sequences within the C9orf72 gene and associated expression control regions (or other directly associated sequences which the disclosure supports the targeting of), then the enablement rejections of claims 95, 112, 115, and 147 may be withdrawn.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AFRICA M MCLEOD whose telephone number is (703)756-1907. The examiner can normally be reached Mon-Fri 9:00AM-6:00PM EST.
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/AFRICA M MCLEOD/ Examiner, Art Unit 1635
/KIMBERLY CHONG/ Primary Examiner, Art Unit 1636
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