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 claims 1, 5, 9, 13, 17, 25, 27, and 30 (Group I) in the reply filed on 03/11/2026 is acknowledged.
Acknowledgment is further made of Applicant’s species election of SEQ ID NOs: 301, 390, 552, and 506. However, upon searching the art, the species election requirement mailed 09/12/2025 is hereby withdrawn.
Claims 31-33, 38, 42, 47, 51-54, 63, and 65 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/11/2026.
Accordingly, claims 1, 5, 9, 13, 17, 25, 27, and 30 are pending and under consideration.
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. The disclosure of provisional application 63/052,881 provides support for the subject matter of instant claims 1, 25, 27, and 30, which are therefore entitled to an effective filing date of 07/16/2020. However, the disclosures of provisional applications 63/052,881 and 63/055,808 do not provide support for the subject matter of instant claims 5, 9, 13, and 17, which are therefore entitled to an effective filing date of 07/16/2021, which is the filing date of PCT/US2021/042100.
Information Disclosure Statement
Receipt of information disclosure statements on 01/13/2023 and 03/11/2026 is acknowledged. The signed and initialed PTO-1449‘s have been mailed with this action.
Drawings
The drawings are objected to because:
With regard to Figures 10A and 10B, there is no Figure 10B in the drawings as indicated at paragraph [0030] of the instant specification. Instead, Figure 10A is listed twice in the drawings. It would be remedial to update the numbering of the drawings such that Figures 10A and 10B are properly identified.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
►Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825 because it does not contain a "Sequence Listing" as a separate part of the disclosure or a CRF of the “Sequence Listing.”. For purposes of examination, the Examiner has searched the sequences listed in PCT/US2021/042100, to which the instant application claims priority as set forth above.
Required response - Applicant must provide:
A "Sequence Listing" part of the disclosure; together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(a)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.821(a)(4); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(a)(3).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
If the "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, applicant must also provide:
A CRF in accordance with 37 CFR 1.821(e)(1) or 1.821(e)(2) as required by 1.825(a)(5); and
A statement according to item 2) a) or b) above.
►Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings. See Figures 11A-C, 12A-D, and 17A-D.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
►Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). See Table 18.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because of the following informalities:
The tables of the instant specification are not listed in proper sequential order. For example, Table 13 is listed on page 34, while Table 2 is listed on page 119 and Table 10 is listed on page 143. It would be remedial to amend the instant specification such that all tables are properly numbered in sequential order.
The quality of Tables 6, 9, 10, and 11 is insufficient to be clearly legible. It would be remedial to amend the instant specification such that the Tables are clearly legible.
Appropriate correction is required.
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.
Claim Interpretation
The Examiner notes that instant claims 5, 9, 13, and 17 all recite “the at least one guide RNA comprises a crRNA sequence,” which under broadest reasonable interpretation may be interpreted such that any sequence with greater than a dinucleotide in common between the instantly claimed sequence and that of the art reads on the instantly claimed sequence. In order to claim the entirety of a sequence, Applicant may amend the instant claims to recite “the at least one guide RNA comprises the crRNA sequence” (bolded emphasis added).
With regard to claim 1, from which all other claims depend, the Examiner notes that instant claim 1 recites a pharmaceutical composition comprising “at least one guide RNA targeting an IL-1α or IL-1β gene” (bolded and underlined emphasis added), the language of which requires targeting one of either IL-1α or IL-1β. The recitations of claims 5 and 13 are drawn to targeting an IL-1α gene, while the recitations of claims 9 and 17 are drawn to targeting an IL-1β gene. However, given that claim 1 requires targeting one of either IL-1α or IL-1β, any pharmaceutical composition targeting IL-1β must also read on the pharmaceutical compositions of claims 5 and 13 targeting IL-1α and any pharmaceutical composition targeting IL-1α must also read on the pharmaceutical compositions of claims 9 and 17 targeting IL-1β, as the instant claim language requires targeting only one of either IL-1α or IL-1β.
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 1, 5, 9, 13, 17, 25, 27, and 30 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.
Claim 1, from which all other claims depend, is drawn to a pharmaceutical composition for the treatment or prevention of a joint disease or condition, said composition comprising a CRISPR gene-editing system comprising an mRNA encoding a Cas9 protein and at least one guide RNA targeting an IL-α or IL-β gene. The rejected claims thus comprise a set of pharmaceutical compositions that must treat or prevent any joint disease or condition. Dependent claims 5, 9, 13, 17, 25, 27, and 30 do not further limit the joint disease or condition to be treated or prevented and therefore inherit the rejection of claim 1.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification describes compositions for treating arthritic joint diseases such as osteoarthritis (Example 1; Example 5) and envisions treatment of any joint disease wherein there are measurable abnormalities in the cells or tissues of the joint that could lead to illness, such as metabolic and molecular derangements triggering anatomical and/or physiological changes in the joint (paragraph [0059]). However, no description is provided of pharmaceutical compositions for treating non-arthritic joint diseases, disorders, or conditions, as is encompassed by the instant claim language.
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claims with regard to structure and function, the examples are only representative of pharmaceutical compositions for treating arthritic joint diseases such as osteoarthritis. The results are not necessarily predictive of treating non-arthritic joint diseases, disorders, or conditions. Thus, it is impossible for one to extrapolate from the few examples described herein those pharmaceutical compositions that would necessarily meet the structural/functional characteristics of the rejected claims.
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of pharmaceutical compositions for treating any joint disease or disorder, including non-arthritic joint diseases, disorders, or conditions, such as tenosynovial giant cell tumor (TGCT) or avascular necrosis (AVN). TGCT is a rare benign disease arising from synovia of joints, bursae, or tendon sheaths that is characterized by both neoplastic and inflammatory processes (Ehrenstein et al., 2017: abstract; page 1476, column 2, paragraph 1), while AVN is characterized by apoptosis of bone cells, resulting in bone collapse with subsequent involvement of the overlying cartilage (Guerado and Caso, 2016: page 516, column 1, paragraph 1). Although both TGCT and AVN lead to complications including osteoarthritis (Ehrenstein et al., 2017: page 1476, column 2, paragraph 1; Guerado and Caso, 2016: page 516, column 1, paragraph 1), treating the secondary osteoarthritis has no impact on the pathophysiology of either TGCT or AVN. Therefore, any treatment for osteoarthritis would not reasonably be expected to treat or prevent joint diseases or disorders such as TGCT or AVN.
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 1, 5, 9, 13, 17, 25, 27, and 30.
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 13 and 25 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.
Claim 13 is drawn to a pharmaceutical composition for the treatment or prevention of a joint disease or condition, said composition comprising a CRISPR gene-editing system comprising an mRNA encoding a Cas9 protein and at least one guide RNA targeting a canine IL-1α gene, wherein said at least one guide RNA is selected from the group consisting of SEQ ID NOs: 522-590. This sequence range overlaps with that recited at instant claim 17, which is drawn to a pharmaceutical composition for the treatment or prevention of a joint disease or condition, said composition comprising a CRISPR gene-editing system comprising an mRNA encoding a Cas9 protein and at least one guide RNA targeting a canine IL-1β gene, wherein said at least one guide RNA is selected from the group consisting of SEQ ID NOs: 497-551. Therefore, as instantly recited, SEQ ID NOs: 522-551 must target both the IL-1α and IL-1β genes. However, as is known to those of ordinary skill in the art, while both IL-1α and IL-1β bind to the same receptor, they share little sequence homology. For example, human IL-1β shares only about 25% homology with human IL-1α (reviewed in Kilian et al., 1986: see abstract). Therefore, while the sequences of IL-1α and IL-1β are known to differ substantially, it is possible to target both species by targeting the region of shared sequence. If such a shared sequence region is targeted, a BLAST search of the guide RNA sequence(s) would return matches to both IL-1α and IL-1β.
However, a BLAST search of SEQ ID NOs: 522 and 523 return matches only to a canine IL-1β gene and not to a canine IL-1α gene, as required by instant claim 13. Representative alignments of the BLAST search results are shown below.
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1113
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Given that SEQ ID NOs: 522 and 523 both BLAST only to a canine IL-1β gene and not to a canine IL-1α gene, it is unclear how SEQ ID NOs: 522 and 523 may target a canine IL-1α gene, as instantly claimed. It would be remedial to clearly identify which sequences target which gene such that one of ordinary skill in the art may be reasonably apprised of the metes and bounds of protection sought by the instant claim set.
Claim 25 recites the limitation "the one or more nucleic acids" in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 25 depends from claim 1, which recites a pharmaceutical composition comprising “an mRNA encoding a...[Cas9] protein…and…at least one guide RNA…”. Not only does claim 1 not recite a generic “nucleic acid” as recited at claim 25, but claim 1 recites an mRNA (i.e. one nucleic acid) and at least one guide RNA (i.e. at least one nucleic acid), meaning claim 1 requires at least two nucleic acid species. For purposes of examination, claim 25 has been interpreted to recite liposomal delivery of at least one of the nucleic acid species recited at instant claim 1 (i.e. either Cas9 or guide RNA(s)). It would be remedial to amend the instant claim language such that there is proper antecedent basis for every claim term.
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.
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.
Claims 1, 5, 9, 25, 27, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Zhao et al., 2019 (hereinafter Zhao) in view of WO 2017/223107 A1 (hereinafter O’Brien; of record), US 2020/0054675 A1 (hereinafter DiPersio), and Givens et al., 2018 (hereinafter Givens), as evidenced by Jiang and Doudna, 2017 (hereinafter Jiang).
With regard to claim 1, which recites “a pharmaceutical composition for the treatment or prevention of a joint disease or condition, comprising: a therapeutically effective amount of a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene-editing system, the system comprising: (i) an mRNA encoding a CRISPR Associated Protein 9 (Cas9) protein; and (ii) at least one guide RNA targeting an IL-1α or IL-1β gene, wherein the target sequence is adjacent to a protospacer adjacent motif (PAM) sequence for the Cas9 protein,” Zhao discloses treatment of arthritis by knocking out IL-1β with CRISPR/Cas9 technology (abstract). Per Zhao, mice were subjected to intra-articular injection of recombinant adeno-associated virus (rAAV) expressing Cas9 derived from Staphylococcus aureus and an sgRNA targeting IL-1β (section “Animal studies and AAV vector preparation” of Methods), which reduced arthritis progression in treated mice (page 677, column 1, paragraph 1; page 677, column 2, paragraph 2). Thus, Zhao discloses a pharmaceutical composition for the treatment of a joint disease or condition, said composition being formulated for intra-articular injection and comprising a therapeutically effective amount of an rAAV expressing Cas9 and an sgRNA targeting IL-1β, as instantly claimed. While Zhao does not specify that the gRNAs taught therein target a sequence adjacent to a PAM sequence for the Cas9 protein, this requirement is fundamental to CRISPR/Cas9 function as is known to those of ordinary skill in the art and taught by Jiang. Per Jiang, target recognition by Cas9 strictly requires the presence of a PAM sequence flanking the target site (abstract). Given that the gRNAs of Zhao are functional (see Figure 1), they must target sites with an adjacent PAM sequence, as taught by Jiang and instantly claimed. Additionally, Zhao does not disclose that the Cas9 is provided as mRNA, as is instantly claimed.
This deficiency is cured by O’Brien. As previously set forth, O’Brien discloses pharmaceutical agents for treating senescence-associated conditions such as arthritis, said pharmaceutical agents comprising gene editing technology such as CRISPR/Cas9, wherein the CRISPR/Cas9 machinery is provided as a nucleic acid such as mRNA encoding said machinery (i.e. the Cas9 and gRNA) (abstract; paragraphs [0002], [0071], and [0082]-[0086]; claims 8 and 9).
Thus, it is considered that Zhao and O’Brien (as evidenced by Jiang) collectively disclose each and every limitation of instant claim 1.
With regard to claim 5, which recites “the at least one guide RNA [of the pharmaceutical composition of claim 1] targets a human IL-1α gene, and the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOs: 298-387,” as set forth above (see section Claim Interpretation), any pharmaceutical composition targeting IL-1β (as disclosed in Zhao) must also read on the pharmaceutical compositions of claim 5, as the instant claim language requires targeting only one of either IL-1α or IL-1β. Thus, it is considered that Zhao discloses each and every additional limitation of instant claim 5.
With regard to claim 9, which recites “the at least one guide RNA [of the pharmaceutical composition of claim 1] targets a human IL-1β gene, and the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOs: 388-496,” as set forth above, Zhao discloses a pharmaceutical composition for the treatment of a joint disease or condition, said composition being formulated for intra-articular injection and comprising a therapeutically effective amount of an rAAV expressing Cas9 and an sgRNA targeting IL-1β, as instantly claimed. However, Zhao does not disclose a guide RNA targeting a human IL-1β gene comprising a crRNA sequence selected from the group consisting of SEQ ID NOs: 388-496, as instantly claimed. This deficiency is cured by DiPersio, which discloses 3 guide RNAs targeting IL-1β (Table 10), including SEQ ID NO: 615, for purposes of treating diseases such as rheumatoid arthritis in human subjects (paragraphs [0249], [0274], and [0282]). As shown in the
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615
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alignment below, SEQ ID NO: 615 of DiPersio is 100% identical to instant SEQ ID NO: 390.
Given the small number of guide RNAs targeting IL-1β disclosed in Table 10 of DiPersio, including SEQ ID NO: 615, which is 100% identical to instant SEQ ID NO: 390, it is considered that DiPersio discloses each and every additional limitation of instant claim 9.
With regard to claim 13, which recites “the at least one guide RNA [of the pharmaceutical composition of claim 1] targets a canine IL-1α gene, and the at least one guide RNA comprises a crRNA sequence selected from the group consisting of SEQ ID NOs: 522-590,” as set forth above (see section Claim Interpretation), any pharmaceutical composition targeting IL-1β (as disclosed in Zhao) must also read on the pharmaceutical compositions of claim 13, as the instant claim language requires targeting only one of either IL-1α or IL-1β. Thus, it is considered that Zhao discloses each and every additional limitation of instant claim 13.
With regard to claim 25, which recites “the pharmaceutical composition of claim 1…comprises one or more liposomes collectively comprising the one or more nucleic acids,” as set forth above (see section Claim Rejections - 35 USC § 112(b)), for purposes of examination, claim 25 has been interpreted to recite liposomal delivery of at least one of the nucleic acid species recited at instant claim 1. One of the nucleic acid species recited at instant claim 1 is “an mRNA encoding a CRISPR Associated Protein 9 (Cas9) protein,” while the other nucleic acid species recited at instant claim 1 is/are “at least one guide RNA.” As disclosed in Givens, cationic liposomes are known to be capable of delivering both Cas9 mRNA and sgRNAs to the nucleus for gene editing (Figure 2). Thus, it is considered that Givens discloses each and every additional limitation of instant claim 25.
With regard to claim 27, which recites “the Cas9 protein [of the pharmaceutical composition of claim 1] is an S. pyogenes Cas9 polypeptide or S. aureus Cas9 polypeptide,” as set forth above, Zhao discloses treatment of arthritis by knocking out IL-1β with CRISPR/Cas9 technology (abstract). Per Zhao, mice were subjected to intra-articular injection of recombinant adeno-associated virus (rAAV) expressing Cas9 derived from Staphylococcus aureus and an sgRNA targeting IL-1β (section “Animal studies and AAV vector preparation” of Methods), which reduced arthritis progression in treated mice (page 677, column 1, paragraph 1; page 677, column 2, paragraph 2). Thus, it is considered that Zhao discloses each and every additional limitation of instant claim 27.
With regard to claim 30, which recites “the pharmaceutical composition of claim 1…is formulated for intra-articular injection within a joint of a subject,” as set forth above Zhao discloses treatment of arthritis by knocking out IL-1β with CRISPR/Cas9 technology (abstract). Per Zhao, mice were subjected to intra-articular injection of recombinant adeno-associated virus (rAAV) expressing Cas9 derived from Staphylococcus aureus and an sgRNA targeting IL-1β (section “Animal studies and AAV vector preparation” of Methods), which reduced arthritis progression in treated mice (page 677, column 1, paragraph 1; page 677, column 2, paragraph 2). Thus, it is considered that Zhao discloses each and every additional limitation of instant claim 30.
Given that Zhao discloses treatment of arthritis by knocking out IL-1β with CRISPR/Cas9 technology, that DiPersio discloses 3 guide RNAs targeting IL-1β (including SEQ ID NO: 615) for purposes of treating diseases such as rheumatoid arthritis in human subjects, and that Givens discloses that cationic liposomes are known to be capable of delivering Cas9 mRNA and sgRNAs to the nucleus for gene editing, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to target IL-1β in human subjects using tailored gRNAs (as in DiPersio) delivered via liposomal (as in Givens) intra-articular injection (as in Zhao) to predictably treat joint diseases or disorders such as arthritis (as in Zhao) in human subjects. One would have been motivated to make such a modification in order to receive the expected benefit of treating joint diseases or disorders such as arthritis in human subjects.
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.
Claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 10 of U.S. Patent No. 11,033,590 B2 (as cited in the IDS filed 03/11/2026) in view of WO 2017/223107 A1 (hereinafter O’Brien; of record).
Claims 1 and 10 of patent ‘590 respectively recite “a pharmaceutical composition for the treatment or prevention of a joint disease or condition, comprising: a therapeutically effective amount of a recombinant adeno-associated virus…comprising one or more nucleic acids encoding a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene-editing system, the system comprising: (i) a CRISPR Associated Protein 9 (Cas9) protein; and (ii) at least one guide RNA targeting an IL-1α gene” or “an IL-1β gene” wherein “the target sequence is adjacent to a protospacer adjacent motif (PAM) sequence for the Cas9 protein.”
In comparison, instant claim 1 recites “a pharmaceutical composition for the treatment or prevention of a joint disease or condition, comprising: a therapeutically effective amount of a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene-editing system, the system comprising: (i) an mRNA encoding a CRISPR Associated Protein 9 (Cas9) protein; and (ii) at least one guide RNA targeting an IL-1α or IL-1β gene, wherein the target sequence is adjacent to a protospacer adjacent motif (PAM) sequence for the Cas9 protein.” Thus, patent ‘590 recites each and every limitation of instant claim 1, with the exception of an mRNA encoding the claimed Cas9 protein. However, this deficiency is cured by O’Brien.
As previously set forth, O’Brien discloses pharmaceutical agents for treating senescence-associated conditions such as arthritis, said pharmaceutical agents comprising gene editing technology such as CRISPR/Cas9, wherein the CRISPR/Cas9 machinery is provided as a nucleic acid such as mRNA encoding said machinery (i.e. the Cas9 and gRNA) (abstract; paragraphs [0002], [0071], and [0082]-[0086]; claims 8 and 9).
Given that patent ‘590 discloses pharmaceutical compositions for the treatment or prevention of a joint disease or condition, said compositions comprising nucleic acids encoding a Cas9 protein and at least one guide RNA targeting either an IL-1α or IL-1β gene, and that O’Brien discloses that mRNA encoding Cas9 is an effective delivery method for expressing Cas9 in treated subjects, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to encode the Cas9 of patent ‘590 in an mRNA molecule (as disclosed in O’Brien) to predictably express Cas9 from said mRNA, thereby targeting either an IL-1α or IL-1β gene for purposes of treating or preventing a joint disease or condition. One would have been motivated to make such a modification in order to receive the expected benefit of treating or preventing a joint disease or condition.
Claims 1 and 30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, and 6 of U.S. Patent No. 11,324,838 B2 (as cited in the IDS filed 03/11/2026) in view of WO 2017/223107 A1 (hereinafter O’Brien; of record).
MPEP 804 II B 1 states:
The specification can be used as a dictionary to learn the meaning of a term in the patent claim. Toro Co. v. White Consol. Indus., Inc., 199 F.3d 1295, 1299, 53 USPQ2d 1065, 1067 (Fed. Cir. 1999)… Further, those portions of the specification which provide support for the patent claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the patent. In re Vogel, 422 F.2d 438, 441-42, 164 USPQ 619, 622 (CCPA 1970).
The following rejections are in view of the decision of the Court of Appeals for the Federal Circuit in Pfizer Inc, v Teva pharmaceuticals USA Inc., 86 USPQ2d 1001, at page 1008 (March 2008), which indicates that there is no patentable distinction between claims to a product and a method of using that product disclosed in the specification of the application and that the preclusion of such a double patenting rejection under 35 USC 121 does not apply where the present application is other than a divisional application of the patent application containing such patentably indistinct claims.
Claim 1 of patent ‘838 recites “a method of treating arthritis in a subject in need thereof, the method comprising: administering, to a joint of the subject, a pharmaceutical composition comprising a pharmaceutically effective amount of a recombinant virus comprising one or more nucleic acids encoding a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene editing system, the system comprising: (i) a CRISPR Associated Protein 9 (Cas9) protein, and; (ii) at least one guide RNA targeting a gene selected from the group consisting of IL-1α, IL-1β, and a combination thereof, wherein:…the target sequence is adjacent to a protospacer adjacent motif (PAM) sequence for the Cas9 protein.” Claims 2 and 6 further limit the treated arthritis to osteoarthritis, which is a joint disease or disorder (as instantly claimed), and the method of administration to intra-articular injection into the joint of the subject.
In comparison, instant claim 1 recites “a pharmaceutical composition for the treatment or prevention of a joint disease or condition, comprising: a therapeutically effective amount of a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene-editing system, the system comprising: (i) an mRNA encoding a CRISPR Associated Protein 9 (Cas9) protein; and (ii) at least one guide RNA targeting an IL-1α or IL-1β gene, wherein the target sequence is adjacent to a protospacer adjacent motif (PAM) sequence for the Cas9 protein.” Thus, patent ‘838 recites each and every limitation of instant claim 1, with the exception of an mRNA encoding the claimed Cas9 protein. However, this deficiency is cured by O’Brien.
As previously set forth, O’Brien discloses pharmaceutical agents for treating senescence-associated conditions such as arthritis, said pharmaceutical agents comprising gene editing technology such as CRISPR/Cas9, wherein the CRISPR/Cas9 machinery is provided as a nucleic acid such as mRNA encoding said machinery (i.e. the Cas9 and gRNA) (abstract; paragraphs [0002], [0071], and [0082]-[0086]; claims 8 and 9).
Furthermore, instant claim 30 recites “the composition [of claim 1] is formulated for intra-articular injection within a joint of a subject,” as recited at claim 6 of patent ‘838.
Given that patent ‘838 discloses a method of administering a pharmaceutical composition (via intra-articular injection) for the treatment or prevention of a joint disease or condition, said compositions comprising nucleic acids encoding a Cas9 protein and at least one guide RNA targeting either or both of an IL-1α or IL-1β gene, and that O’Brien discloses that mRNA encoding Cas9 is an effective delivery method for expressing Cas9 in treated subjects, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to encode the Cas9 of patent ‘838 in an mRNA molecule (as disclosed in O’Brien) to predictably express Cas9 from said mRNA, thereby targeting either an IL-1α or IL-1β gene for purposes of treating or preventing a joint disease or condition. One would have been motivated to make such a modification in order to receive the expected benefit of treating or preventing a joint disease or condition.
Claims 1, 25, 27, and 30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4-8, 10-12, 14-18, and 20 of U.S. Patent No. 12,290,572 B2 (as cited in the IDS filed 03/11/2026) in view of WO 2017/223107 A1 (hereinafter O’Brien; of record).
Claims 1 and 11 of patent ‘572 respectively recite “a pharmaceutical composition for the treatment or prevention of a joint disease or condition, comprising: a therapeutically effective amount of a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene-editing system, the system comprising: (i) a nucleic acid encoding a CRISPR Associated Protein 9 (Cas9); and (ii) at least one guide RNA targeting an IL-1α gene,” or “an IL-1β gene,” “wherein…the target sequence is adjacent to a protospacer adjacent motif (PAM) sequence for the Cas9 protein.” Claims 2 and 12 of patent ‘572 recite that “the composition comprises one or more liposomes collectively comprising the CRISPR gene-editing system.” Claims 4 and 14 limit the Cas9 polypeptide to “an S. pyogenes Cas9 polypeptide,” while claims 5 and 15 limit the Cas9 polypeptide to “an S. aureus Cas9 polypeptide.” Claims 6-8 and 16-18 respectively recite targeting human, canine, or equine IL-1α and IL-1β genes, all of which read on the instantly claimed guide RNA targeting IL-1α or IL-1β genes, as set forth in greater detail below. Finally, claims 10 and 20 recite formulation “for intra-articular injection within a joint of a subject.”
In comparison, instant claim 1 recites “a pharmaceutical composition for the treatment or prevention of a joint disease or condition, comprising: a therapeutically effective amount of a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene-editing system, the system comprising: (i) an mRNA encoding a CRISPR Associated Protein 9 (Cas9) protein; and (ii) at least one guide RNA targeting an IL-1α or IL-1β gene, wherein the target sequence is adjacent to a protospacer adjacent motif (PAM) sequence for the Cas9 protein.” Thus, both the instant and patented applications are drawn to a pharmaceutical composition for the treatment or prevention of a joint disease or condition, wherein said composition comprises an encoded Cas9 protein and at least one guide RNA targeting either an IL-1α or IL-1β gene, wherein the target sequence is adjacent to a protospacer adjacent motif (PAM) sequence for the Cas9 protein. Although the patented application does not disclose that the Cas9 is specifically encoded in an mRNA molecule, this deficiency is cured by O’Brien.
As previously set forth, O’Brien discloses pharmaceutical agents for treating senescence-associated conditions such as arthritis, said pharmaceutical agents comprising gene editing technology such as CRISPR/Cas9, wherein the CRISPR/Cas9 machinery is provided as a nucleic acid such as mRNA encoding said machinery (i.e. the Cas9 and gRNA) (abstract; paragraphs [0002], [0071], and [0082]-[0086]; claims 8 and 9).
Furthermore, instant claim 25 recites that “the composition [of claim 1] comprises one or more liposomes collectively comprising the one or more nucleic acids,” as recited at claims 1 and 11 of patent ‘572. Instant claim 27 limits the claimed Cas9 protein to S. pyogenes or S.aureus Cas9, as recited at claims 4, 5, 14, and 15 of patent ‘572. Finally, instant claim 30 recites “the composition [of claim 1] is formulated for intra-articular injection within a joint of a subject,” as recited at claims 10 and 20 of patent ‘572.
Given that patent ‘572 discloses a method of administering a pharmaceutical composition (via intra-articular injection) for the treatment or prevention of a joint disease or condition, said compositions comprising nucleic acids encoding a Cas9 protein and at least one guide RNA targeting either or both of an IL-1α or IL-1β gene, and that O’Brien discloses that mRNA encoding Cas9 is an effective delivery method for expressing Cas9 in treated subjects, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to encode the Cas9 of patent ‘572 in an mRNA molecule (as disclosed in O’Brien) to predictably express Cas9 from said mRNA, thereby targeting either an IL-1α or IL-1β gene for purposes of treating or preventing a joint disease or condition. One would have been motivated to make such a modification in order to receive the expected benefit of treating or preventing a joint disease or condition.
Claims 1, 25, 27, and 30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4-8, 10-12, 14-18, and 20 of U.S. Patent No. 12,419,968 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
Claims 1 and 11 of patent ‘968 respectively recite “a pharmaceutical composition for the treatment or prevention of a joint disease or condition, comprising: a therapeutically effective amount of a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene-editing system, the system comprising: (i) an mRNA encoding a CRISPR Associated Protein 9 (Cas9) protein; and (ii) at least one guide RNA targeting an IL-1α” or “an IL-1β gene”, “wherein:…the target sequence is adjacent to a protospacer adjacent motif (PAM) sequence for the Cas9 protein.” Claims 2 and 12 of patent ‘968 recite that “the composition comprises one or more liposomes collectively comprising the CRISPR gene-editing system.” Claims 4 and 14 limit the Cas9 polypeptide to “an S. pyogenes Cas9 polypeptide,” while claims 5 and 15 limit the Cas9 polypeptide to “an S. aureus Cas9 polypeptide.” Claims 6-8 and 16-18 respectively recite targeting human, canine, or equine IL-1α and IL-1β genes, all of which read on the instantly claimed guide RNA targeting IL-1α or IL-1β genes, as set forth in greater detail below. Finally, claims 10 and 20 recite formulation “for intra-articular injection within a joint of a subject.”
In comparison, instant claim 1 recites “a pharmaceutical composition for the treatment or prevention of a joint disease or condition, comprising: a therapeutically effective amount of a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene-editing system, the system comprising: (i) an mRNA encoding a CRISPR Associated Protein 9 (Cas9) protein; and (ii) at least one guide RNA targeting an IL-1α or IL-1β gene, wherein the target sequence is adjacent to a protospacer adjacent motif (PAM) sequence for the Cas9 protein.” Thus, both the instant and copending applications are drawn to a pharmaceutical composition for the treatment or prevention of a joint disease or condition, wherein said composition comprises an mRNA-encoded Cas9 protein and at least one guide RNA targeting either an IL-1α or IL-1β gene, wherein the target sequence is adjacent to a protospacer adjacent motif (PAM) sequence for the Cas9 protein.
Furthermore, instant claim 25 recites that “the composition [of claim 1] comprises one or more liposomes collectively comprising the one or more nucleic acids,” as recited at claims 1 and 11 of patent ‘968. Instant claim 27 limits the claimed Cas9 protein to S. pyogenes or S.aureus Cas9, as recited at claims 4, 5, 14, and 15 of patent ‘968. Finally, instant claim 30 recites “the composition [of claim 1] is formulated for intra-articular injection within a joint of a subject,” as recited at claims 10 and 20 of patent ‘968.
Thus, the pharmaceutical compositions of patent ‘968 and the instant application are not patentably distinct.
Claims 1, 5, 9, 13, 17, 27, and 30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 4, 7, 10, 13, 16, 19, 22, 25-27, 32, and 53 of copending Application No. 17/867,486 (reference application; corresponds to US 2023/0235321 A1; claims amended 11/19/2025). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 1 of copending application ‘486 recites “a composition for the treatment or prevention of a joint disease or condition, comprising one or more lipid nanoparticles (LNP) collectively comprising: (i) an RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease; and (ii) at least one guide RNA or a nucleic acid encoding at least one guide RNA targeting an IL-1α gene or an IL-1β gene, wherein the guide RNA specifically binds a target sequence that is adjacent to a protospacer adjacent motif (PAM) sequence for the RNA-guided nuclease.”
Copending claims 26 and 27 respectively recite that “the RNA-guided nuclease is a CRISPR associated protein 9 (Cas9) protein” derived from “S. pyogenes or S. aureus,” as recited at instant claim 27.
Copending claim 32 recites that “the RNA-guided nuclease…is mRNA encoding the RNA-guided nuclease,” as recited at instant claim 1 and set forth in greater detail below.
Instant claim 1 recites “a pharmaceutical composition for the treatment or prevention of a joint disease or condition, comprising: a therapeutically effective amount of a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene-editing system, the system comprising: (i) an mRNA encoding a CRISPR Associated Protein 9 (Cas9) protein; and (ii) at least one guide RNA targeting an IL-1α or IL-1β gene, wherein the target sequence is adjacent to a protospacer adjacent motif (PAM) sequence for the Cas9 protein.”
Finally, copending claim 53 recites that “the composition is formulated for intra-articular injection within a joint of a subject,” as recited at instant claim 30.
Copending claim 3 recites specific targets within “the IL-1α gene or the IL-1β gene,” all of which read on the instantly claimed targeting of an IL-1α gene or an IL-1β gene., as set forth above regarding instant claim 1.
Copending claims 4, 7, 10, 13, 16, 19, 22, and 25 recite specific crRNA sequences targeting an IL-1α gene or an IL-1β gene in various species, all of which read on the instantly claimed targeting of an IL-1α gene or an IL-1β gene, as set forth in greater detail below.
With specific regard to copending claims 4 and 7, which respectively recite targeting a human IL-1α gene or a human IL-1β gene with crRNA sequences selected from the group consisting of SEQ ID NOs: 168-187, 298-387, and 681-710 or SEQ ID NOs: 188-201, 388-496, and 711-740, SEQ ID NOs: 301 and 390 of both the copending and instant applications are identical. As shown in the alignment of Appendix I, copending and instant SEQ ID NO: 301 targeting a human IL-1α gene are identical to each other, and copending and instant SEQ ID NO: 390 targeting a human IL-1β gene are identical to each other. These sequence identifiers are recited at instant claims 5 and 9 and are not patentably distinct from the recitation of copending claims 4 and 7.
With specific regard to copending claims 10 and 13, which respectively recite targeting a canine IL-1α gene or a canine IL-1β gene with crRNA sequences selected from the group consisting of SEQ ID NOs: 202-216, 552-590, and 741-770 or SEQ ID NOs: 217-235, 497-551, and 771-800, SEQ ID NOs: 552 and 506 of both the copending and instant applications are identical. As shown in the alignment of Appendix II, copending and instant SEQ ID NO: 552 targeting a canine IL-1α gene are identical to each other, and copending and instant SEQ ID NO: 506 targeting a canine IL-1β gene are identical to each other. These sequence identifiers are recited at instant claims 13 and 17 and are not patentably distinct from the recitation of copending claims 10 and 13.
Thus, the compositions of application ‘486 and the instant application are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1 and 25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 70-72, and 96 of copending Application No. 18/832,443 (corresponds to US 2025/0228969 A1; claims amended 08/04/2025) in view of Lo et al., 1996 (hereinafter Lo), as evidenced by Jiang and Doudna, 2017 (hereinafter Jiang).
Claim 1 of copending application ‘443 recites “a pharmaceutical composition for treating or preventing a joint disorder, comprising: (i) an RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease; and (ii) at least one guide RNA or a nucleic acid encoding at least one guide RNA targeting a gene associated with the production, blocking, or removal or reactive oxygen species (ROS),” with specific recitation of targeting an NF-κB gene.
Copending claim 70 recites that the RNA-guided nuclease is provided as “mRNA encoding the RNA-guided nuclease,” while copending claims 71 and 72 limit the RNA-guided nuclease to “a Cas protein,” specifically “a Cas9 protein.”
Finally, copending claim 96 recites that “the pharmaceutical composition…comprises one or more liposomes collectively comprising the (i)…nucleic acid encoding the RNA-guided nuclease, and (ii) at least one guide RNA…”.
In comparison, instant claim 1 recites “a pharmaceutical composition for the treatment or prevention of a joint disease or condition, comprising: a therapeutically effective amount of a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene-editing system, the system comprising: (i) an mRNA encoding a CRISPR Associated Protein 9 (Cas9) protein; and (ii) at least one guide RNA targeting an IL-1α or IL-1β gene, wherein the target sequence is adjacent to a protospacer adjacent motif (PAM) sequence for the Cas9 protein.”
Thus, while both the instant and copending applications are drawn to pharmaceutical compositions for treating or preventing a joint disorder, said compositions comprising an mRNA-encoded Cas9 and at least one guide RNA, the copending application does not recite at least one guide RNA targeting either IL-1α or IL-1β, as instantly claimed. However, IL-1 species including IL-1β are known to be involved in the production of ROS, as reviewed in Lo (abstract; page 15704, column 1, paragraph 1).
With regard to the claimed targeting of a sequence adjacent to a PAM sequence, while not explicitly recited in the copending application, this requirement is fundamental to CRISPR/Cas9 function as is known to those of ordinary skill in the art and taught by Jiang. Per Jiang, target recognition by Cas9 strictly requires the presence of a PAM sequence flanking the target site (abstract).
Furthermore, instant claim 25 recites “the composition [of claim 1] comprises one or more liposomes collectively comprising the one or more nucleic acids,” as recited at copending claim 96 and set forth above.
Given that copending application ‘443 discloses pharmaceutical compositions for treating or preventing a joint disorder, said compositions comprising an mRNA-encoded Cas9 and at least one guide RNA targeting a gene associated with the production of ROS (wherein the target sequence is adjacent to a PAM sequence as taught in Jiang), and that Lo discloses that IL-1 species such as IL-1β are known to be involved in the production of ROS, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the pharmaceutical composition of copending application ‘443 to comprise at least one guide RNA targeting IL-1 species such as IL-1β to predictably reduce ROS production facilitated by IL-1β, thereby treating a joint disorder. One would have been motivated to make such a modification in order to receive the expected benefit of reducing ROS production facilitated by IL-1β, thereby treating a joint disorder.
This is a provisional nonstatutory double patenting rejection.
Claims 1 and 27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 and 34-37 of copending Application No. 18/856,005 (reference application; corresponds to US 2025/0263681 A1; claims amended 08/14/2025) in view of Zhao et al., 2019 (hereinafter Zhao).
Claim 1 of copending application ‘005 recites “a pharmaceutical composition for treating a disorder, the composition comprising a plurality of lipid nanoparticles (LNPs) encapsulating: (i) an RNA-guided nuclease or a nucleic acid encoding an RNA-guided nuclease; and (ii) at least one guide RNA or a nucleic acid encoding at least one guide RNA targeting a gene selected from…IL1A [and] IL1B…”. Copending claim 34 further recites that the nucleic acid encoding an RNA-guided nuclease “is mRNA encoding the RNA-guided nuclease.” Furthermore, copending claims 35-37 respectively recite that “the RNA-guided nuclease is a Cas protein” such as “a Cas9 protein”, “wherein the Cas9 protein is an S. pyogenes Cas9 polypeptide.”
In comparison, instant claim 1 recites “a pharmaceutical composition for the treatment or prevention of a joint disease or condition, comprising: a therapeutically effective amount of a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene-editing system, the system comprising: (i) an mRNA encoding a CRISPR Associated Protein 9 (Cas9) protein; and (ii) at least one guide RNA targeting an IL-1α or IL-1β gene, wherein the target sequence is adjacent to a protospacer adjacent motif (PAM) sequence for the Cas9 protein.”
Thus, both the instant and copending applications recite identical pharmaceutical compositions with the exception of the copending application reciting treatment of any disorder, while the instant application recites treatment of any joint disorder. This deficiency is cured by Zhao. As set forth above, Zhao discloses treatment of arthritis by knocking out IL-1β with CRISPR/Cas9 technology (abstract).
Given that the copending application discloses a pharmaceutical composition for the treatment of any disorder, said pharmaceutical composition comprising an mRNA encoding S. pyogenes Cas9 and at least one guide RNA targeting IL-1α or IL-1β, and that Zhao discloses treatment of the joint disorder arthritis via CRISPR/Cas9-mediated knockout of IL-1β, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to apply the pharmaceutical composition of the copending application to the treatment of joint disorders such as arthritis to predictably treat arthritis, as disclosed in Zhao. One would have been motivated to make such a modification in order to receive the expected benefit of treating joint disorders such as arthritis.
This is a provisional nonstatutory double patenting rejection.
Claim 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 10-13, and 65 of copending Application No. 19/318,731 (reference application; not yet published) in view of WO 2017/223107 A1 (hereinafter O’Brien; of record).
Claim 1 of copending application ‘731 recites “a pharmaceutical composition for the treatment or prevention of a joint disease or condition comprising a gene-editing system, wherein said gene-editing system targets at least one locus related to joint function,” wherein said locus is limited at copending claim 2 to “one or more of IL-1α, and/or IL-1β.”
Copending claims 10-13 respectively recite that “the gene-editing [of the pharmaceutical composition of claim 1] comprises the use of a programmable nuclease that mediates the generation of a double-strand or single-strand break…” “wherein the gene-editing comprises…a CRISPR method,” wherein the CRISPR method is a CRISPR-Cas9 method.
Finally, copending claim 65 recites “a pharmaceutical composition, comprising: a therapeutically effective amount of a Clustered Regularly Interspaced Short palindromic Repeats (CRISPR) gene editing complex comprising a CRISPR Associated Protein 9 (Cas9) and at least one guide RNA targeting the gene, wherein the gene is selected from the group consisting of IL-1α, IL-1β, and a combination thereof…”.
In comparison, instant claim 1 recites “a pharmaceutical composition for the treatment or prevention of a joint disease or condition, comprising: a therapeutically effective amount of a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene-editing system, the system comprising: (i) an mRNA encoding a CRISPR Associated Protein 9 (Cas9) protein; and (ii) at least one guide RNA targeting an IL-1α or IL-1β gene, wherein the target sequence is adjacent to a protospacer adjacent motif (PAM) sequence for the Cas9 protein.” Thus, both the instant and copending applications are drawn to a pharmaceutical composition for the treatment or prevention of a joint disease or condition, wherein said composition comprises an encoded Cas9 protein and at least one guide RNA targeting either an IL-1α or IL-1β gene, wherein the target sequence is adjacent to a protospacer adjacent motif (PAM) sequence for the Cas9 protein. Although the copending application does not disclose that the Cas9 is specifically encoded in an mRNA molecule, this deficiency is cured by O’Brien.
As previously set forth, O’Brien discloses pharmaceutical agents for treating senescence-associated conditions such as arthritis, said pharmaceutical agents comprising gene editing technology such as CRISPR/Cas9, wherein the CRISPR/Cas9 machinery is provided as a nucleic acid such as mRNA encoding said machinery (i.e. the Cas9 and gRNA) (abstract; paragraphs [0002], [0071], and [0082]-[0086]; claims 8 and 9).
Given that copending application ‘731 discloses a pharmaceutical composition for the treatment or prevention of a joint disease or condition, said compositions comprising a Cas9 protein and at least one guide RNA targeting either or both of an IL-1α or IL-1β gene, and that O’Brien discloses that mRNA encoding Cas9 is an effective delivery method for expressing Cas9 in treated subjects, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to encode the Cas9 of copending application ‘731 in an mRNA molecule (as disclosed in O’Brien) to predictably express Cas9 from said mRNA, thereby targeting either an IL-1α or IL-1β gene for purposes of treating or preventing a joint disease or condition. One would have been motivated to make such a modification in order to receive the expected benefit of treating or preventing a joint disease or condition.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
The instant application discloses a number of guide RNA sequences targeting canine IL-1α and IL-1β. Upon searching the prior art, the only matches to the instantly claimed guide RNAs either pre-date CRISPR technology or do not specify targeting canine genes.
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WO 2015/128651 A1 (hereinafter Hunt) discloses siRNA molecules targeting canine IL-1β to treat canine arthritis (abstract; Table 5). As shown in the alignment below, SEQ ID NO: 9 of Hunt is 90% identical to instant SEQ ID NO: 506.
However, siRNAs and guide RNAs are fundamentally different molecules. As disclosed in Hunt, siRNAs are double stranded RNA fragments that silence gene expression in a sequence-specific manner (page 2, paragraph 4). In comparison, guide RNAs are single stranded RNA fragments comprising a target sequence-specific spacer portion and a tracrRNA for forming a complex with the Cas nuclease (reviewed in Jiang and Doudna, 2017: see Figure 2). While both siRNA and guide RNA design are routinely practiced in the field, the disclosure of an siRNA does not anticipate or motivate a guide RNA, as siRNAs and guide RNAs are fundamentally different molecules, both structurally and functionally.
►WO 2020/028533 A1 (hereinafter Chen) discloses compositions and methods for identification of membrane targets for enhancement of T cell activity against a disease, disorder or condition, and/or enhancing T cell anti-tumor activity in human subjects (abstract; page 3, paragraphs 11 and 12). As part of the compositions and methods taught therein, Chen discloses 4 guide RNAs targeting IL-1α, including SEQ ID NO: 1726 (Table 1), which is 100% identical to instant
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SEQ ID NO: 553, as shown in the alignment below.
However, Chen discloses treatment of human subjects with no disclosure of canine subjects, as in the instant claim set. Furthermore, a BLAST search of SEQ ID NO: 1726 of Chen does not return canine matches. Therefore, it cannot be reasonably considered that Chen discloses a guide RNA targeting a canine IL-1α gene and at least one gRNA comprising a crRNA sequence selected from SEQ ID NO: 522-590, as instantly claimed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sarah E Allen whose telephone number is (571)272-0408. The examiner can normally be reached M-Th 8-5, F 8-12.
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/SARAH E ALLEN/ Examiner, Art Unit 1637
/J. E. ANGELL/ Primary Examiner, Art Unit 1637
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