DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This action is in response to the amendment, filed 12/22/2025, in which claims 133, 135 and 136 were cancelled, claims 121, 123-125, 127, 131, 134 and 137-140 were amended, and claims 142 and 143 were added. Claims 121-127, 130-132, 134, 137-140, 142 and 143 are pending.
Applicant’s arguments have been thoroughly reviewed, but are not persuasive for the reasons that follow. Any rejections and objections not reiterated in this action have been withdrawn. This action is FINAL.
Election/Restrictions
Applicant elected Group I and the species of CD274 AIC pre-mRNA, disease associated with CD274, and the sequence of SEQ ID NO: 68 without traverse in the reply filed 8/5/2024.
The species election requirement for an election of one sequence identifier from SEQ ID NOS: 1-68 and 72-76 was withdrawn in the prior action. The remainder of the requirement is maintained.
Claims 121-127, 130-132, 134, 137-140, 142 and 143 are under consideration.
Information Disclosure Statement
Receipt of information disclosure statements is acknowledged. The signed and initialed PTO-1449s have been mailed with this action.
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 – 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 the nucleic acid sequence in Fig. 3.
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.
Response to Arguments - Sequence Disclosures
Applicant's arguments filed 12/22/2025 have been fully considered but they are not persuasive. The response does not specifically address the sequence compliance issue, and the issue has not been corrected by amendment to the drawings or specification.
Specification
The use of the terms TAQMAN (paragraphs [00205] and [00206]), and TRUSEQ (paragraphs [00202] and [00207]), which are trade names or marks used in commerce, have been noted in this application. Each term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Response to Arguments - Specification
Applicant's arguments filed 12/22/2025 have been fully considered but they are not persuasive. The response does not specifically address the objection to the specification, and the specification has not been corrected by amendment.
Claim Objections
Claim 121 is objected to because of the following informalities:
1) At line 9, the word “and” should be deleted from the claim to improve the grammar.
2) At line 8, the phrase “comprises of at least 8” should be amended to recite “comprises at least 8” to improve the grammar.
Appropriate correction is required.
Claim 139 is objected to because of the following informalities: the phrase “disease or condition comprises” should be amended to recite “disease or condition comprising” to improve the grammar of the claim. Appropriate correction is required.
Response to Arguments – Claim Objections
The previous objection to claim 121 has been withdrawn in view of Applicant’s amendment to the claim in the reply filed 12/22/2025.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 142 and 143 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. This is a new rejection, necessitated by the addition of new claims 142 and 143 in the reply filed 12/22/2025.
The term “+100 relative to the 5’ splice site of the alternative-intron to -100 relative to the 3’ splice site of the alternative-intron” in claim 142 is a relative term which renders the claim indefinite. Claim 142 depends from claim 121, which indicates that alternative-intron-containing (AIC) pre-mRNA contains the AIC within an exon of a CD274 pre-mRNA having a sequence with at least 80% sequence identity to SEQ ID NO: 68. The instant specification indicates that SEQ ID NO: 68 is CD274 exon 4 (e.g., Table 2). CD274 is also referred to as PD-L1 (e.g., paragraph [0003]). The disclosure does not define the location of the 5’ and 3’ splice sites of AIC of exon 4 of CD274. Fig. 1 contains a schematic of the AIC of exon 4 of CD274 but does not provide sequence information for the splice sites. Table 3 provides a list of exemplary genes, including the coordinates of the alternative intron. However, this table does not contain information for CD274/PD-L1. Without a disclosure of the location of the 5’ and 3’ splice sites of the AIC of Exon 4 of CD274, one would not know which sequences are +100 or -100 relative to these undefined sites. One of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
The term “+1 to +30 relative to the 3’ splice site of the alternative-intron” in claim 143 is a relative term which renders the claim indefinite. Claim 143 depends from claim 121, which indicates that alternative-intron-containing (AIC) pre-mRNA contains the AIC within an exon of a CD274 pre-mRNA having a sequence with at least 80% sequence identity to SEQ ID NO: 68. The instant specification indicates that SEQ ID NO: 68 is CD274 exon 4 (e.g., Table 2). CD274 is also referred to as PD-L1 (e.g., paragraph [0003]). The disclosure does not define the location of the 3’ splice site of AIC of exon 4 of CD274. Fig. 1 contains a schematic of the AIC of exon 4 of CD274 but does not provide sequence information for the splice sites. Table 3 provides a list of exemplary genes, including the coordinates of the alternative intron. However, this table does not contain information for CD274/PD-L1. Without a disclosure of the location of the 3’ splice site of the AIC of Exon 4 of CD274, one would not know which sequences are +1 to +30 relative to the undefined site. One of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
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.
The following is a new rejection, necessitated by the amendment filed 12/22/2025:
Claim 122 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 122 depends from claim 121 and recites, “wherein the therapeutic agent inhibits exclusion of the alternative-intron from the AIC pre-mRNA and increases a level of a processed mRNA that comprises the alternative-intron, the first portion of the exon and the second portion of the exon, thereby increasing expression of the target protein or the target RNA in the cells.” Claim 121 recites, “whereby exclusion of the alternative-intron from the AIC pre-mRNA encoding the target protein or the target RNA is inhibited, thereby increasing a level of processed mRNA encoding the target protein or the target RNA, and increasing expression of the target protein or the target RNA in the cells.” Thus, claim 122 does not add a further limitation to claim 121. 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.
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.
Claim 123 is 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. This is a new matter rejection.
In the reply filed 12/22/2025, claim 123 was amended to recite, “wherein the ASO comprises a sequence that is complementary to at least 8 contiguous bases of the sequence according to residues 61-271 of SEQ ID NO: 68 or residues 563-772 of SEQ ID NO: 69.”
The specification provides literal support for therapeutic agents that are ASOs that consist of 8 to 50 nucleobases (e.g., paragraphs [0031] and [00155]). The disclosure provides support for the ASOs consisting of 18 nucleobases of SEQ ID NOS: 1-67 that target the CD274 gene (e.g., paragraph [0077], including Table 1; paragraph [00204]; Fig. 3; sequence listing). The specification indicates that SEQ ID NO: 68 is the sequence of CD274 exon 4 (e.g., Table 2). The specification indicates that SEQ ID NO: 69 is CD274 mRNA NCBI Reference Sequence NM_014143.3. The disclosure does not provide literal support for ASOs complementary to the claimed ranges of nucleotides of SEQ ID NO: 68 or 69.
Figure 3 shows an ASO-walk of ASOs of SEQ ID NOS: 1-67 targeting exon 4 of the CD274 gene (e.g., Example 3). SEQ ID NO: 1 (Sbjct) aligns with nucleotides 85-68 of SEQ ID NO: 68 (Query):
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SEQ ID NO: 64 (Sbjct) aligns with nucleotides 271-254 of SEQ ID NO: 68 (Query):
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Thus, the disclosure provides support for ASOs that are complementary to 18 contiguous bases of residues 68-251 of SEQ ID NO: 68. The disclosure does not provide support for oligos of at least 8 contiguous bases of the sequence according to residues 61-271 of SEQ ID NO: 68.
SEQ ID NO: 1 (Sbjct) aligns with nucleotides 587-570 of SEQ ID NO: 69 (Query):
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SEQ ID NO: 63 (Sbjct) aligns with nucleotides 771-754 of SEQ ID NO: 69 (Query):
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SEQ ID NO: 64 (Sbject) aligns with nucleotides 773-756 of SEQ ID NO: 69 (Query):
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Thus, the disclosure provides support for ASOs that are complementary to 18 contiguous bases of residues 570-771 or 570-773 of SEQ ID NO: 69. The specifically claimed ranges lack support in the original disclosure.
The original specification, drawings and claims were thoroughly reviewed and no support could be found for the amendment. Accordingly, the amendment is a departure from the disclosure as originally filed, and Applicant has not pointed to a specific portion of the original disclosure that provides support.
Claims 121-127, 130-132, 134, 137-140, 142 and 143 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of increasing expression of CD274, comprising contacting cells in vitro with an antisense RNA oligomer, where the antisense RNA oligomer is antisense to the sequence of nucleotides 218-235 of SEQ ID NO: 68, the sequence of nucleotides 243-260 of SEQ ID NO: 68, or the sequence of nucleotides 248-265 of SEQ ID NO: 68, does not reasonably provide enablement for making any therapeutic agent or vector encoding a therapeutic agent capable of inhibiting exclusion or an alternative-intron in an exon of CD274 pre-mRNA, using any of SEQ ID NO: 1-67, sequences with 8 to 50 nucleobases complementary to the sequence of SEQ ID NO: 68, introducing a premature termination codon (PTC) or simulating nonsense mediated decay (NMD) to increase expression of CD274 RNA or protein, carrying out the method with a cell in vivo, or treating any disease or condition, including any condition associated with PD-L1 deficiency. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. This rejection was made in the Office action mailed 8/21/2025 and has been rewritten to address the amendment to the claims in the reply filed 12/2/2025.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: Claims 121-127, 130-132, 134, 137-140, 142 and 143 are drawn to a method of modulating expression of a target protein by cells having an alternative-intron-containing pre-mRNA (AIC pre-mRNA), the AIC pre-mRNA comprising an alternative-intron, a first portion of an exon flanking a 5’ splice site of the alternative-intron, and a second portion of the exon flanking a 3’ splice site of the alternative-intron. The method comprises the step of “contacting the cells with a therapeutic agent or a vector encoding the therapeutic agent, and wherein the therapeutic agent is an antisense oligomer (ASO) comprising between 8 and 50 nucleobases; wherein the ASO comprises of at least 8 contiguous bases that are complementary to the sequence according to SEQ ID NO: 68; wherein the ASO binds to a targeted region of the AIC pre-mRNA encoding the target protein, whereby exclusion of the alternative-intron from the AIC pre-mRNA encoding the target protein or the target RNA is inhibited, thereby increasing a level of processed mRNA encoding the target protein or the target RNA, and increasing expression of the target protein or the target RNA in the cells; wherein the targeted region of the AIC pre-mRNA is located within an exon of a CD274 pre-mRNA having a sequence with at least 80% sequence identity to SEQ ID NO: 68.” Dependent claim 123 requires the ASO to comprise a sequence that is complementary to at least 8 contiguous bases of the sequence according to residues 61-271 of SEQ ID NO: 68 or residues 563-772 of SEQ ID NO: 69. Dependent claim 124 requires at least a portion of the targeted region of the AIC pre-mRNA to be within the alternative intron. Dependent claim 125 requires the expressed protein to be a full-length protein and/or a fully functional protein. Dependent claim 127 requires the splicing of the alternative intron from the AIC pre-RNA to result in a processed mRNA that encodes a non-functional target protein. Dependent claim 130 requires contacting the cell with the vector encoding the therapeutic agent, wherein the vector is a viral vector. Dependent claim 131 requires contacting the cell with the therapeutic agent. Dependent claim 132 requires the ASO to comprise a backbone modification, a modified sugar moiety, or both. Dependent claim 134 limits the ASO to one that has a sequence selected from the group consisting of SEQ ID NOs: 1-67. Dependent claim 137 requires the targeted region of the pre-mRNA to comprise at least 10 contiguous nucleobases of SEQ ID NO: 68. Dependent claim 138 requires the targeted region of the pre-mRNA to overlap with a junction of the first portion of the exon and the alternative intron or overlap with a junction of the alternative intron and the second portion of the exon. Dependent claim 139 requires the method to treat a subject suffering from a disease or condition that comprises an immune disease or an immune disorder. The nature of the invention is complex in that one must be able to make the ASOs and use the ASOs to inhibit exclusion of an alternative intron within exon 4 of the CD274 gene to result in increased expression of CD274 protein or RNA within the cell. Additionally, the requirement that the agents have therapeutic activity further complicates the nature of the invention in that the administration must provide a therapeutic outcome for any disease or condition in any subject.
Dependent claim 126 requires the splicing of the alternative intron from the AIC pre-mRNA to produce a processed mRNA with a premature termination codon (PTC) and/or that undergoes nonsense-mediated decay (NMD). The nature of the invention is further complicated by this limitation in that claim 126 depends from claim 121, which requires increasing expression of the target protein or the target RNA in the cells, whereas NMD would result in decay of the RNA.
Dependent claims 142 and 143 define the targeted region of the CD274 AIC pre-mRNA relative to splice sites of the alternative-intron. The nature of the invention is further complicated by these limitations, because the disclosure does not identify the position or sequence of the splice sites. Thus, one would not know where the specified positions of the dependent claims are relative to a pre-mRNA with a sequence at least 80% identical to SEQ ID NO: 68.
Claim 140 is drawn to a method of treating a disease or condition associated with PD-L1 deficiency in a subject in need thereof by increasing expression of a target protein in a cell of the subject. The method comprises the step of contacting a cell of the subject with a therapeutic agent or a vector encoding the therapeutic agent, wherein the therapeutic agent is an antisense oligomer (ASO) comprising between 8 to 50 nucleobases, wherein the ASO comprises at least 8 contiguous bases complementary to the sequence according to SEQ ID NO: 68, wherein the ASO inhibits exclusion of an alternative-intron from an alternative-intron-containing pre-mRNA (AIC pre-mRNA) encoding the target protein or the target RNA, wherein the AIC pre-mRNA comprises the alternative-intron, a first portion of an exon flanking a 5' splice site of the alternative-intron, a second portion of the exon flanking a 3' splice site of the alternative-intron, wherein the ASO binds to a targeted region of the AIC pre-mRNA encoding the target protein or the target RNA, whereby splicing of the alternative-intron from the AIC pre-mRNA encoding the target protein or the target RNA inhibited, thereby increasing a level of processed mRNA encoding the target protein or the target RNA and increasing the expression of the target protein in the cell of the subject, wherein the targeted portion of the AIC pre-mRNA is located within an exon 4 of a CD274 pre-mRNA having a sequence with at least 80% sequence identity to SEQ ID NO: 68. The nature of the invention is complex in that one must be able to make and use the ASOs to result in increased expression of CD274 protein. Additionally, the requirement that the agents have therapeutic activity further complicates the nature of the invention in that the administration must provide a therapeutic outcome for any disease or condition associated with PD-L1 deficiency in any subject.
Breadth of the claims: The claims broadly encompass the administration of any ASO between 8 to 50 nucleobases in length with at least 8 contiguous bases that are complementary to the sequence of SEQ ID NO: 68.
The location of the cell is unspecified. The specification teaches that the cell can be in a subject or isolated from a subject (ex vivo) or in culture (in vitro) (e.g., paragraphs [00158] and [00186]). However, the administered agent is defined as a “therapeutic.” Thus, the cell is reasonably interpreted as a cell present in an organism in need of treatment. The claim broadly encompasses the treatment of any disease or condition. Dependent claim 139 limits the disease or condition to any immune disease or immune disorder. Independent claim 140 specifies the treatment of any disease or condition associated with PD-L1 deficiency.
The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the specification and existence of working examples: The specification teaches that PD-L1 (CD274) is a ligand for PD-1 (CD279), which is a critical immunoregulatory checkpoint molecule that has profound effects on adaptive immune responses, specifically T cell function (e.g., paragraphs [0004] and [0074]). The specification teaches that PD-L1 interacts with PD-1 to send inhibitory signal to invading T cells to induce anergy and suppress T cell responses (e.g., paragraphs [0004]-[0005] and [0071]-[0072]).
The specification envisions the treatment of a disease or condition in a subject in need thereof by modulating expression of a target protein or target RNA in the cell of a subject, such as when the target protein is PD-L1 (CD274) (e.g., paragraphs [0008], [0011] and [0073]). The specification envisions that the disease or condition is an immune disease or an immune disorder, such as an autoimmune disorder, an inflammatory disease, an inflammatory disorder, a chronic infection, graft versus-host disease (GVHD), a transplant rejection, or a T cell proliferative disorder, multiple sclerosis, inflammatory bowel disease, autoimmune hepatitis, kidney inflammation, rheumatoid arthritis, psoriasis, lupus nephritis, corneal transplant or uveitis, for example, as well as any autosomal dominant disorder, autosomal recessive disorder, X-linked dominant disorder, X-linked recessive disorder, Y-linked disorder, mitochondrial disease, or multifactorial or polygenic disorder (e.g., paragraphs [0025], [0069], [00163]-[00170] and [00174]-[00178]).
The specification envisions therapeutic agents, such as small molecules and antisense oligomer (ASO) complementary to the AIC pre-mRNA (e.g., paragraphs [0061] and [00116]). The specification asserts that the ASOs targeting CD274 gene of Table 1 are useful for increasing production of PD-L1 by targeting a region of a CD274 AIC pre-mRNA (e.g., paragraph [0077]). Table 1 lists the ASOs of #1-67 as SEQ ID NOS: 1-67, respectively; however, the recited sequences of the sequence identifiers are DNA sequences and not the 2' -O-MOE RNA with PS backbone tested in the working examples (e.g., Examples 3-5). Further, the specification envisions using ASOs known in the art, such as those disclosed in WO 2015/035091 (e.g., paragraph [00116]; WO 2015/035091 A1, cited as reference 064 on an IDS filed 3/8/2022). The specification envisions the use of any ASO capable of hybridizing to a pre-mRNA, and modifications of those ASO (e.g., paragraphs [00116]-[00140], [00155]-[00162]). The specification provides general guidance regarding the formulation of ASOs into pharmaceutical compositions and administration of the compositions (e.g., paragraphs [00179]-[00191]).
The specification teaches the use of screening methods, such as an ASO “walk” or ASO “micro-walk,” to identify ASOs that hybridize to a pre-mRNA and modulate splicing (e.g., paragraphs [00192]-[00199]).
Example 1 is directed to the identification of alternative-introns in CD274 transcripts by sequencing RNA obtained from AST (human astrocyte) cells. Exon 4 in CD274 was identified as having a potential alternative-intron. The alternative intron is shown graphically in Fig. 1, and removal of the alternative-intron results in a premature termination codon (PTC) and a non-functional protein.
Example 2 demonstrates the removal of the alternative intron (a.i.) from the CD274 pre-mRNA in Huh7 cells treated with cycloheximide to inhibit nonsense-mediated mRNA decay. Figs. 2A and 2B show the full length (can) and spliced (a.i.) products. Fig. 2C shows the presence of the alternatively spliced transcript in ARPE-19, HUVEC and cyno retinal cells.
Example 3 details the design of an ASO-walk targeting exon 4 (SEQ ID NO: 68) of CD274, where the +68 to +253 was targeted with 2' -O-MOE RNA, PS backbone, 18-mer ASOs shifted by 5-nucleotide intervals. See also Fig. 3. The ASOs created in Example 3 were screened in ARPE-19 cells for the ability to reduce the percentage of transcripts containing the alternative-intron. Fig. 4A shows a higher band corresponding to the full length (can) mRNA, and a lower band corresponding to the shorter a.i. mRNA. Fig. 4B shows the quantification of RT-PCR products plotted as a percentage of the alternative-intron (a.i./(can+a.i.))*100. The specification states the following with regard to the results of the screening assay:
ASOs were denoted as possible candidate when the relative abundance of a.i was decreased. Treatment with ASO 34, for example, correlates to a decreased relative abundance compared to a control (mock). Fig 4C shows Taqman qPCR analysis using RNA from samples in panel A The Taqman probe is positioned over the exon 3-exon 4 junction. As observed, CD274 mRNA expression has a general inverse correlation with the relative abundance of the a.i. transcript. ASO 34, for example, show an increase in CD274 expression compared to control.
Thus, ASO 34 was selected as a candidate in example 4.
Example 5 demonstrates that the selected ASO, ASO 34, was capable of reducing the amount of the a.i. product in transfected Huh7 cells. The specification states the following with regard to the results:
Results show a higher relative abundance of full length can mRNA in ASO 34 transfected cells as compared to the mock transfected cells. FIG 5D shows the mean fluorescent intensity of a flow cytometry analysis of Huh7 cells transfected for 5 days with 80 nM ASO 34 plotted as fold change over control (mock) to quantify the expression of PD-L 1 protein.
Thus, Example 5 confirms the activity of ASO 34 (SEQ ID NO: 34) in a second cell type.
Example 6 is a prophetic example directed to the detection of additional alternative introns and screening for ASO that alter splicing.
No working example is provided where ASO 34 or any other agent or vector encoding the agent is administered to a disease model or subject for the purpose of treating a disease or condition.
Predictability and state of the art: The instant disclosure supports the unpredictability of the claimed invention. Example 3 directed to the design of ASOs of SEQ ID NO: 1-67, which are named ASO1-ASO67, respectively. See Example 3 and Table 1 at pages 22-24. In Example 4 the ASOs were screened for the ability to reduce the removal of the alternative-intron such that more full-length processed mRNA would be produced. Examples 4 and 5 indicate that ASO34 is capable of reducing the removal (inhibits exclusion or decreases splicing) of the alternative-intron. Most of the tested ASOs do not have the ability to reduce the removal of the alternative intron and increase production of the full length transcript/protein.
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Examples 4 and 5 indicate that ASO34 is able to reduce the removal of the alternative-intron (Fig. 4B) and increase levels of the full-length transcript (Fig. 4C). Based on this result ASOs, such as AS01-14 clearly were not able to carry out the claimed function of increasing expression of the protein by modulating splicing of the alternative-intron. ASO41 and AS042 may be able to function as claimed with modulation of splicing and increased expression of the protein. The results in the instant specification demonstrate that merely knowing the placement of an alternative-intron within an exon is not sufficient for the design of an ASO that has the claimed function. Whether any one ASO has the ability to modulate splicing to maintain an alternative intron within a processed mRNA and provide increased expression of CD274 was unpredictable.
The prior art teaches the application of the same ASO “walk” and ASO “micro-walk” procedures to identify ASOs capable of increasing protein expression in cells by promoting the splicing of a retained intron (e.g., Krainer et al. US Patent Application Publication No. 2016/0298121 A1, cited as reference 232 on an IDS filed 3/8/2022; paragraphs [0004], [0179] and [0183]). Thus, the prior art teaches molecules of the same general structure as those tested in the instant specification (e.g., paragraph [0196] teaching 18-mer 2’-O-Me RNA with PS backbone) are capable of having the opposite effect as presently claimed. The prior art teaches promotion of splicing to remove retained introns to improve protein expression (e.g., paragraph [0004]), whereas the instant disclosure teaches reducing splicing to keep a retained intron to improve CD274 protein expression (e.g., ASO34 of Examples 4 and 5). Other prior art (Guccione et al. WO 2019/004939 A1, cited as reference 6 on the IDS filed 5/21/2024) teaches antisense oligonucleotides that would hybridize to nucleotides to SEQ ID NO: 68 (sequence listing, SEQ ID NOS: 20567-23695 are antisense to PD-L1 exons 4 and 5). One of these sequences named 0915_319_2OM_E4 for PD-L1, SEQ ID NO: 20993) is shown in Tables 1 and 2. However, Guccione et al teach that generally antisense oligonucleotides can be used to promote exon skipping or retention (page 1, 2nd paragraph; page 6, 3rd paragraph; page 25, 1st paragraph), and no specific function is taught for any of the oligonucleotides antisense to PD-L1 (CD274) exon 4. Thus, one of skill in the art would have recognized the unpredictability in selecting untested ASOs to modulate splicing of CD274 pre-mRNA to retain an alternative-intron to increase CD274 protein expression.
One would have also recognized the difficulty in translating results from cell-based screening assays to in vivo results. Godfrey et al (EMBO Molecular Medicine, Vol. 9, No. 5, pages 545-557, 2017; cited in a prior action) teaches the following with regard to pre-clinical development of antisense oligonucleotides (AONs) at page 552, left column, 2nd full paragraph:
Both in vitro and in vivo models are required for pre-clinical testing of new AONs. It is generally accepted that while in vitro models provide data on the AON mechanism of action and efficacy, in vivo models are better suited to assess the delivery of the compound. Therefore, most AON sequence variants are pre-screened in vitro and only candidates deemed promising are then progressed to in vivo screening (Fig 4).
Fig. 4 of Godfrey shows that cell cultures are used for proof of concept, and screening/selection of sequences, whereas disease-specific animal models are used to assess efficacy, toxicity and target delivery. Additionally, van Ommen (New Biotechnology, Vol. 30, No. 3, pages 299-301, March 2013; cited in a prior action) teaches that there are technical difficulties and safety issues related to vector-based gene therapy, and the most advanced approach entails intervening with the splicing apparatus by administering antisense oligonucleotides (e.g., page 299, left column, 1st paragraph). One would have recognized the unpredictability in moving from cell-based screening to therapeutic applications without testing for efficacy, toxicity and the ability to target the appropriate cell types in an animal model of the specific disease being treated. One would have also recognized the unpredictability of translating success with an antisense oligonucleotide to a vector-encoded therapy.
The specification teaches that it would have been unpredictable to treat all diseases or conditions with the therapeutic agents of the claims. The specification teaches that PD-L1 (CD274) is upregulated in a broad group of tumors, where its presence suppresses anti-tumor T cell responses (e.g., paragraph [0004]). The claims require increased expression of target protein (i.e., CD274 protein) in the cells. Thus, it would have been unpredictable to treat tumor diseases or conditions with the claimed method. One would expect that reducing anti-tumor T cell responses to be detrimental to the subject with the tumor disease or condition. Further, Pei et al (Journal of Medicinal Chemistry, Vol. 60, pages 6461-6479, April 2017; cited in a prior action) teaches that PD-L1 inhibitors are currently in clinical development to modulate the immune system, such as for the treatment of cancer and potentially other disease, such as viral infection (e.g., page 6470, paragraph bridging columns).
Amount of experimentation necessary: The quantity of experimentation required to carry out the full scope of the claimed invention is large. One could select the ASO sequence of ASO 34, 41 or 42 as a lead compound in the development of a therapeutic agent and test the selected ASO sequence for the ability to be delivered to the appropriate cell type in a quantity sufficient to see a therapeutic benefit in an animal model specific for the selected disease. This process would need to be repeated for each of the different diseases and conditions to be treated. Further experimentation would be required to identify additional ASO agents capable of performing the claimed functions as therapeutic agents, and to identify vectors capable of delivering the therapeutic in an effective and safe manner. More experimentation would need to be conducted to identify other therapeutic agents other than antisense oligonucleotides, such as small molecules. The process of cell-based screening and further study to achieve a therapeutic effect in an animal model would be required for each agent and each disease to be treated.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claims 121-127, 130-132, 134, 137-140, 142 and 143 are not considered to be fully enabled by the instant disclosure.
Claims 121-127, 130-132, 134, 137-140, 142 and 143 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. This rejection was made in the Office action mailed 8/21/2025 and has been rewritten to address the amendment to the claims in the reply filed 12/2/2025.
The claims require the provision of a genus of therapeutic agents and vectors encoding the therapeutic agents, where the therapeutic agent is an antisense oligomer (ASO) comprising between 8 to 50 nucleobases, wherein the ASO comprises at least 8 contiguous bases that are complementary to the sequence of SEQ ID NO: 68. The ASOs must function as a therapeutic and be capable of increasing the expression of CD274 protein in a cell by inhibiting exclusion of the alternative intron within exon 4 of the CD274 gene. In contrast, claim 126 requires the processed mRNA to have a premature termination codon (PTC) and/or undergo nonsense mediated decay (NMD). The therapeutic agent may be of any structure, such as a small molecule, protein, antibody, or nucleic acid. Dependent claim 132 requires the antisense oligomer to comprise a backbone modification, a modified sugar moiety, or both. Thus, the dependent claims limit the structure to a genus of antisense oligomer molecules of any sequence capable of performing the claimed functions or defined as being an ASO of 8-50 bases with at least 8 bases complementary to SEQ ID NO: 68. Thus, the claims encompass a genus of ASOs that must function to inhibit exclusion of an alternative intron within exon 4 of CD274, which is represented by SEQ ID NO: 68, where the alteration in splicing has various effects on CD274 production and can provide a therapeutic outcome for any disease or disorder, including any immune disease or disorder, including those associated with a deficiency of PD-L1.
Dependent claim 134 requires the antisense oligomer to have a sequence selected from the group consisting of SEQ ID Nos: 1-67. This claim requires the ASO to have a specific sequence, which according to the sequence listing is a DNA sequence. Each ASO must be able to function to inhibit exclusion of an alternative intron within exon 4 of CD274, which is represented by SEQ ID NO: 68, where the alteration in splicing has various effects on CD274 production and can provide a therapeutic outcome for any disease or disorder, including any immune disease or disorder, including those associated with a deficiency of PD-L1.
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 does not describe any agents with demonstrated therapeutic activity for any disease or condition. The specification describes an antisense RNA oligomer, where the antisense RNA oligomer is antisense to the sequence of nucleotides 218-235 of SEQ ID NO: 68, the sequence of nucleotides 243-260 of SEQ ID NO: 68, or the sequence of nucleotides 248-265 of SEQ ID NO: 68, where each of the antisense oligomers are capable of inhibiting exclusion/decreasing splicing of an alternative-intron within exon 4 of the CD274 pre-mRNA and increasing CD274 expression (e.g., Table 1; Examples 3-5). Note that the sequences of SEQ ID NOS: 1-67 are not RNA oligomers, as each is set forth as DNA. No description is provided of any other agents capable of modulating splicing of an alternative intron within any exon of CD274 and increasing CD274 expression.
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 an antisense RNA oligomer, where the antisense RNA oligomer is antisense to the sequence of nucleotides 218-235 of SEQ ID NO: 68, the sequence of nucleotides 243-260 of SEQ ID NO: 68, or the sequence of nucleotides 248-265 of SEQ ID NO: 68 for use in vitro. The results are not necessarily predictive of other antisense oligomers with the same function. Fig. 4 of the instant disclosure demonstrates the unpredictability in designing antisense oligomers that have the claimed functions. Most texted antisense oligomers across exon 4 of the CD274 gene were unable to function as claimed. Thus, it is impossible for one to extrapolate from the few examples described herein those antisense oligomers or other agents 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. The prior art teaches the application of the same ASO “walk” and ASO “micro-walk” procedures to identify ASOs capable of increasing protein expression in cells by promoting the splicing of a retained intron (e.g., Krainer et al. US Patent Application Publication No. 2016/0298121 A1, cited as reference 232 on an IDS filed 3/8/2022; paragraphs [0004], [0179] and [0183]). Thus, the prior art teaches molecules of the same general structure as those tested in the instant specification (e.g., paragraph [0196] teaching 18-mer 2’-O-Me RNA with PS backbone) are capable of having the opposite effect as presently claimed. The prior art teaches promotion of splicing to remove retained introns to improve protein expression (e.g., paragraph [0004]), whereas the instant disclosure teaches reducing splicing to keep a retained intron to improve CD274 protein expression (e.g., ASO34 of Examples 4 and 5). Thus, one of skill in the art would have recognized the unpredictability in selecting untested ASOs to modulate splicing of CD274 pre-mRNA to retain an alternative-intron to increase CD274 protein expression.
The prior art teaches the underdeveloped and unpredictable nature of developing small molecules that regulate splicing or applying splice-modulating agents to therapeutic applications. Taladriz-Sender et al (Methods, Vol. 167, pages 134-142, June 14, 2019) teaches that to identify a small molecule capable of modulating the splicing of SMN2, the PTC/Roche team used a cell-based high-throughput screening platform to screen 200,000 small molecules for the ability to induce exon 7 inclusion (e.g., paragraph bridging pages 137-138). Taladriz-Sender et al teach that a lead compound was identified in the cell-based screen but did not induce a measurable increase in SMN2 production in patient-derived fibroblasts, and further modifications and testing were required to develop a small molecule capable of increasing SMN protein in vivo (e.g., paragraph bridging pages 137-138). Taladriz-Sender et al teach that the Novartis team carried out similar high-throughput screen to identify lead compounds, one of which was functional in a mouse model (e.g., page 138, left column, full paragraph). One would have recognized the unpredictability in making small molecules that promote exonic inclusion. One would have also recognized the difficulty in translating results from cell-based screening assays to in vivo results. Godfrey et al (EMBO Molecular Medicine, Vol. 9, No. 5, pages 545-557, 2017) teaches the following with regard to pre-clinical development of antisense oligonucleotides (AONs) at page 552, left column, 2nd full paragraph:
Both in vitro and in vivo models are required for pre-clinical testing of new AONs. It is generally accepted that while in vitro models provide data on the AON mechanism of action and efficacy, in vivo models are better suited to assess the delivery of the compound. Therefore, most AON sequence variants are pre-screened in vitro and only candidates deemed promising are then progressed to in vivo screening (Fig 4).
Fig. 4 of Godfrey shows that cell cultures are used for proof of concept, and screening/selection of sequences, whereas disease-specific animal models are used to assess efficacy, toxicity and target delivery. Additionally, van Ommen (New Biotechnology, Vol. 30, No. 3, pages 299-301, March 2013) teaches that there are technical difficulties and safety issues related to vector-based gene therapy, and the most advanced approach entails intervening with the splicing apparatus by administering antisense oligonucleotides (e.g., page 299, left column, 1st paragraph). One would have recognized the unpredictability in moving from cell-based screening to therapeutic applications without testing for efficacy, toxicity and the ability to target the appropriate cell types in an animal model of the specific disease being treated. One would have also recognized the unpredictability of translating success with an antisense oligonucleotide to a vector-encoded therapy.
Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is’’). As discussed above, the skilled artisan cannot envision the detailed chemical structure of therapeutic agents, including therapeutic antisense oligomers, and written description requires more than a potential method of obtaining the agents. The compound itself is required. See Fiers v. Revel, 25USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 13 USPQ2d 1016.
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 121-127, 130-132, 134, 137-140, 142 and 143.
Response to Arguments - 35 USC § 112
The rejection of claim 135 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is moot in view of Applicant’s cancellation of the claim in the reply filed 12/22/2025.
The rejection of claims 134, 137 and 139 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, has been withdrawn in view of Applicant’s amendment to the claims in the reply filed 12/22/2025.
The rejection of claim 125 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, has been withdrawn in view of Applicant’s amendment to the claim in the reply filed 12/22/2025. The new matter has been removed from the claim.
The rejection of claim 134 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, has been withdrawn in view of Applicant’s amendment to the claim in the reply filed 12/22/2025. The new matter has been removed from the claim.
The rejection of claim 137 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, has been withdrawn in view of Applicant’s amendment to the claim in the reply filed 12/22/2025. The reference to essential subject matter present in an electronic database has been removed from the claim.
The rejection of claims 133, 135 and 136 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is moot in view of Applicant’s cancellation of the claims in the reply filed 12/22/2025.
With respect to the rejection of claims 121-127, 130-132, 134, 137-140, 142 and 143 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, Applicant's arguments filed 12/22/2025 have been fully considered but they are not persuasive.
The response asserts that the rejection fails to properly weigh the limited scope of the amended claims, the high level of skill in the art, and the specification’s detailed guidance for making and using the claimed antisense oligomers. The response notes that claim 121 was amended to recite “and wherein the therapeutic agent is an antisense oligomer (ASO) comprising between 8 to 50 nucleobases; wherein the ASO comprises of at least 8 contiguous bases complementary to the sequence according to SEQ ID NO: 68.” The response asserts that the rejection ignores the significant limitations in the amended claims, which now: (1) target a specific gene (CD274); (2) focus on a defined region (exon 4 of CD274 pre-mRNA); (3) limit the therapeutic antisense agent to antisense oligomers of 8-50 nucleobases; and (4) require at least 8 contiguous bases complementary to SEQ ID NO: 68. The response asserts that the focused scope creates a subset so narrow that a skilled artisan would readily appreciate the breadth of the claimed invention without undue experimentation. The response asserts that one would have been enabled to practice the claimed invention, because PD-L1 protein deficiency is well-recognized in the art as associated with diabetes and autoimmune diseases, as described in paragraph [0089]. The response asserts that Applicant has provided multiple examples of ASO design and ASOs that cannot achieve exclusion of the alternative intron from the AIC pre-mRNA fall outside the claim scope.
These arguments are not found persuasive. The claims are drawn to contacting a cell in vitro or in vivo with an antisense oligomer of 8-50 bases that has at least 8 contiguous bases complementary to the sequence of SEQ ID NO: 68 (exon 4 of the CD274 gene) to inhibit exclusion of sequence from an exon and to increase expression of CD274 protein. The antisense oligomer is broadly claimed and includes claims to antisense oligomers that have been shown by the disclosure not to have the claimed functions. For example, see claim 134, which is directed to each of SEQ ID NOS: 1-67, yet the disclosure shows that each of the sequences does not have the claimed functions with regard to retention of the alternate intron and increased expression of CD274 (e.g., Figs. 4B and 4C). Example 3 directed to the design of ASOs of SEQ ID NO: 1-67, which are named ASO1-ASO67, respectively. See Example 3 and Table 1 at pages 22-24. In Example 4 the ASOs were screened for the ability to reduce the removal of the alternative-intron such that more full-length processed mRNA would be produced. Each of the tested ASOs is an 18-mer with 2’-MOE RNA and phosphorothioate backbone (e.g., Example 3). Each of these ASOs was not shown to have the claimed function in vitro, and the claims are much broader with respect to the length, degree of complementarity and modifications. Additionally, the specification does not provide evidence of in vivo efficacy in any disease model. Thus, the limitations that have been added to the claims are not sufficient to fully enable the claimed invention.
The response asserts that the rejection fails to address the relatively high skill in the art.
This argument is not found persuasive. See the paragraph bridging pages 12-13 of the action mailed 8/21/2025. The level of one of ordinary skill in the art was considered with regard to the claims. It is agreed that the level of skill is high. Thus, it was not a relevant factor to be discussed in more detail. The high skill of one in the art cannot overcome the unpredictable nature of the invention as evidenced by the data provided in the specification and teachings of the prior art (see the action mailed 8/21/2025 at pages 20-24).
Thus, the rejection is maintained.
The rejection of claims 133, 135 and 136 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, is moot in view of Applicant’s cancellation of the claims in the reply filed 12/22/2025.
With respect to the rejection of claims 21-127, 130-132, 134, 137-140, 142 and 143 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, Applicant's arguments filed 12/22/2025 have been fully considered but they are not persuasive.
The response asserts that the scope of the claimed invention is well-described by the as-filed specification. The response asserts that the Office’s position is internally inconsistent, because the Office concedes that applicant has provided “several examples of how to design, identify and use the ASOs to apply the claimed function.” The response asserts that the Office contradictorily argues that Applicant “has not shown possession of the invention and merely claim[s] a function.”
These arguments are not found persuasive. The response does not provide specific support for the breadth of the claimed invention by the as-filed specification. Further, the quoted phrases could not be located in the rejection of record. Thus, Applicant has not demonstrated an internally inconsistent position.
The response notes that the claim scope has been narrowed. Further, the response asserts “applicant has provided an example with 67 ASOs that were designed to identify which ASOs would lead to an increase in expression.” The response asserts that Applicant has provided working examples even though they are not necessary.
These arguments are not found persuasive. Designing ASOs that can be tested for the claimed functions does not satisfy the written description requirement. First, only a few of the tested ASOs have the claimed function in cells in vitro (e.g., Examples; Fig. 4), yet the claims encompass all of these ASOs, and specifically claim the ASO sequences that do not work, and also claim each of the ASOs as DNA, rather than the tested RNA. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is’’).
Thus, the rejection is maintained.
Conclusion
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.
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Jennifer Dunston
Supervisory Patent Examiner
Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
Prosecution Insights