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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/21/2025 has been entered.
Response to Amendment
The amendment filed 7/21/2025, amending claim 1 and cancelling claims 4, 7, 18, 33, and 34 is acknowledged. Claims 1-3, 5, 6, and 9 are pending and under examination. Applicant’s amendments to the claims have overcome each and every 112(a) and 112(d) rejection previously set forth in the Final Office Action mailed 1/24/2025.
In light of the cited prior art below, e.g. Ohe and Havens, the Examiner rejoins non-elected species SEQ ID NO: 268 with the elected species SEQ ID NO: 263.
Response to Arguments
Applicant's arguments filed 7/21/2025 have been fully considered but they are not persuasive. The Applicant has filed a Declaration (Lutz; 07.21.2025). The Examiner acknowledges and has considered the Lutz Declaration filed under 37 CFR §1.132 on 7/21/2025. The statements by Lutz in the Declaration were not found to be persuasive.
The Applicant argues that “the Declaration provides evidence that SMOs comprising each of these sequences are effective at modulating RAGE pre-mRNA splicing in a murine animal model”. The Declaration describes evaluating the efficacy of candidate SMOs by injecting neonatal RAGE transgenic mice with bilateral SMO or saline, then measuring the expression of membrane bound RAGE and sRAGE. The Declaration provides evidence of treatment with both hRG3 and hRG16 yielding a reduction of mbRAGE while increasing sRAGE. It is unclear how to evaluate the disclosure of the Declaration filed 7/21/2025 on its merits as it relates to the claimed invention. Additionally, the Declaration refers to Panels A and B, which are not found in the disclosure. Further, there is no disclosure of instant SEQ ID NOs: 263 or 268, nor any explanation of how the disclosure of the Declaration relates to the instant case or rejections set forth in the Final Office Action mailed 1/24/2025.
Claim Rejections - 35 USC § 112(a) – Written Description
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 2 and 3 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.
Claims 2 and 3 recite the method of modulating splicing of a RAGE pre-mRNA and claimed SMO has the function of increasing (claim 2) or decreasing (claim 3) the amount of mRNA encoding a soluble isoform of RAGE protein produced.
Either these are inherent property(ies) of (that naturally flows from) the method and claimed SMO of claim 1, or they are not.
The claim denotes that not all of the structures/method steps of the independent claim are able to achieve the functional property(ies) recited in the dependent claim(s).
To the extent it is not an inherent property (that naturally flows) from the product/method of the independent claim, then something must change. The claim is considered to lack adequate written description for failing to recite the structure that is necessary and sufficient to cause the recited functional language.
The limitations “wherein the SMO increases the amount of mRNA encoding a soluble isoform of RAGE protein produced” and “wherein the SMO decreases the amount of mRNA encoding a membrane bound isoform of RAGE protein” merely state a functional characteristic without providing any indication about how the functional characteristic is provided. The functional characteristic does not follow from (is not an inherent property of) the structure recited in the claim, so it is unclear whether the claim requires some other structure to be added to the composition to provide the functional characteristic. The specification fails to disclose what structural changes to the method of modulating splicing of a RAGE pre-mRNA and/or claimed SMO is necessary and sufficient to cause the recited functions of claims 2 and 3, and thus the ordinary artisan would not know what modification(s) must be made in order to fulfill the instant recitation.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. 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 complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The claims fail to recite, and the specification fails to disclose, a nexus between the required method step of contacting a plurality of cells with a SMO comprising the sequences of SEQ ID NO: 263 or 268 and the corresponding functional property(ies) of increasing (claim 2) or decreasing (claim 3) the amount of mRNA encoding a soluble isoform of RAGE protein produced.
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, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not clarify the nature of the corresponding structure(s) and/or method step(s) that is/are necessary and sufficient to cause the recited functional language.
Claim Rejections - 35 USC § 112(d)
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.
Claims 2 and 3 are 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 2 recites “wherein the SMO increases the amount of mRNA encoding a soluble isoform of RAGE protein produced”. Claim 3 recites “wherein the SMO decreases the amount of mRNA encoding a membrane bound isoform of RAGE protein”.
Either these are inherent property(ies) of (that naturally flows from) the method of claim 1, or it is not, and something of the method of independent claim 1 must change.
Either these therapeutic results are inherent properties of (that naturally flow from) the method step of contacting a plurality of cells with a splice modulating oligonucleotide (SMO) comprising the sequence of SEQ ID NO: 263 or SEQ ID NO: 268, or they are not, and something of the method of independent claim 1 must change.
Furthermore, in regard to instant claims 2 and 3, it is noted that the wherein clauses do not recite any additional structure(s) and/or active method steps, but simply states a characterization or conclusion of the results of structure and/or active method step positively recited (e.g. contacting a plurality of cells with a splice modulating oligonucleotide (SMO) comprising the sequence of SEQ ID NO: 263 or SEQ ID NO: 268). Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.").
Thus, on its face, claims 2 and 3 fail to limit claim 1. For examination purposes, claims 2 and 3 are interpreted to share the same limitations as claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1-3, 5, 6, and 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ohe (Ohe, Kazuyo, et al. "Regulation of alternative splicing of the receptor for advanced glycation end products (RAGE) through G-rich cis-elements and heterogenous nuclear ribonucleoprotein H." The journal of biochemistry 147.5 (2010): 651-659.) and further in view of Havens (Havens, Mallory A., and Michelle L. Hastings. "Splice-switching antisense oligonucleotides as therapeutic drugs." Nucleic acids research 44.14 (2016): 6549-6563.).
Ohe teaches the construction of a RAGE minigene in order to identify G-rich cis-elements within exon 9B for regulation of the alternative splicing of RAGE, with the alternative splicing resulting in an increase in the esRAGE/mRAGE ratio in minigene-transfected cells (i.e., in vitro – claim 5) (Abstract). Ohe teaches the alternatively spliced mRNAs being generated by alternative 5’ splice site selection in intron 9 (Fig. 1). To create the RAGE minigene, a RAGE genomic sequence from the 3’ part of exon 8 to the 3’ flanking region of exon 11 (nucleotides 8572-9960 of GenBank D28769, a copy of which is included) was used (pg. 652, “Construction of RAGE minigene”). In Fig. 2 of Ohe, the first and last nucleotides of RAGE exons are numbered (the nucleotide numbers are based on the genomic sequence starting from the first ATG of exon 1; e.g., position 2618 in Figs. 2A and 3A corresponds to position 9280 in GenBank D28769). Ohe designates position 2618 in the figures as a splice site that produces mRAGE.
Positions 9257-9270 of GenBank D28769 correspond to the 5’ to 3’ binding site for SEQ ID NO: 263 (e.g., the reverse compliment of SEQ ID NO: 263 – “AACC…”) (see bottom line of attached GenBank D28769 NPL and image below), while position 9262-9285 of GenBank D28769 correspond to the 5’ to 3’ binding site for SEQ ID NO: 268 (e.g., the reverse compliment of SEQ ID NO: 268 – “GGCG…”) (see top line of attached GenBank D28769 NPL and image below). Positions 9256-9282 of GenBank D28769 are noted to correspond to exon 9 of RAGE. As such, instant SEQ ID NOs: 263 and 268 correspond to 5’ binding sites of exon 9 of RAGE (since both are found to bind to sites at the beginning of exon 9).
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Havens teaches the use of splice-switching oligonucleotides (SSOs) (aka SMOs) as therapeutic drugs. Table 1 of Havens teaches numerous examples of SMOs targeting 5’ splice sites of a gene of interest being used in vivo (claim 6) (i.e., SMO is administered to a subject with a disease or condition such as cancer – claim 9) for skipping an exon of interest (e.g., target gene ERBB4, targeting exon 26 5’ss (exon skipping); target gene MDM4, targeting exon 6 5’ss (exon skipping); target gene GYS2, targeting exon 6 5’ss (exon skipping); etc.).
It would have been obvious to one of ordinary skill before the effective filing date of the current invention to apply the knowledge that SMOs can be used to target a 5’ splice site in order to induce exon skipping, per Havens, to the alternative splicing of RAGE at exon 9 (in order to skip exon 10 of RAGE, resulting in a decrease the amount of mRAGE/increase the amount of sRAGE created), as taught by Ohe. One would have a reasonable degree for success because Havens teaches a multitude of SMOs targeting a 5’ splice site in different target genes and different target exons successfully resulting in the skipping of an exon of interest. Additionally, One would be motivated to apply the teachings of Havens to the alternative site-splicing of RAGE taught by Ohe in order to alter/regulate the ratio of mRAGE to sRAGE present, as the balance of expressions of the two RAGE products generated by alternative splicing, cytotoxic mRAGE and cytoprotective esRAGE, is considered to be associated with susceptibility/resistance to RAGE-related disorders such as cancer (pg. 657, col 2, para 2).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
As mentioned above, instant SEQ ID NOs: 263 and 268 are located in exon 9 of RAGE, specifically near a 5’ splice site. As such, the suggestion in the art (e.g., by Havens and Ohe) to target 5’ splicing sites to induce exon skipping, and to target a 5’ splice site in exon 9 of RAGE encompasses the claimed invention. Further, the instant specification discloses:
“SMOs of the invention are typically about, for example, 10-200 nucleotides long (e.g., 12-175, 14-150, 15-125, 20-100, or 25-75). In specific examples, the SMO sequence is 14 to about 26 nucleotides long (e.g., about 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 nucleotides long). In some instances, only a portion of an SMO hybridizes to the pre-mRNA, and that portion has the requisite level of complementarity to support hybridization of the SMO to the pre-mRNA. Thus, for example, a portion of an SMO that hybridizes to pre-mRNA may comprise, e.g., about 12-100 nucleotides, while the SMO molecule itself may comprise additional nucleotides, e.g., 1-100, 2-80, 3-70, 4-60, 5-50, 6-40, 7-30, 8-20, or 10-15 additional nucleotides” (pg. 13).
Since the specification of the claimed invention permits the SMOs to be 10-200 nts in length, and the claims recite “comprising the sequence of SEQ ID NO: 263 or SEQ ID NO: 268”, SMOs within 100 nts before or after the 5’ splice site of exon 9 of RAGE would overlap with the instantly claimed SMOs. Therefore, the teachings of Ohe and Havens encompasses and substantially overlaps with the claimed SMOs.
Further, the instant application fails to disclose an element of criticality for instant SEQ ID NOs: 263 and 268 (e.g., why must these nucleotides of exon 9 of RAGE specifically be targeting for splicing? Why would targeting other regions of exon 9 not produce the same result), as opposed to other 5’ splice sites of exon 9 of RAGE as taught by Ohe and Havens (i.e., why/how does the targeting of a region with SEQ ID NOs: 263 and 268 result in a structural/functional difference compared to the prior teachings in the art of the general technique/concept of targeting 5’ splice sites with SMOs for exon skipping in a gene of interest?).
The "mere existence of differences between the prior art and an invention does not establish the invention's nonobviousness." Dann v. Johnston, 425 U.S. 219, 230, 189 USPQ 257, 261 (1976). The gap between the prior art and the claimed invention may not be "so great as to render the [claim] nonobvious to one reasonably skilled in the art."
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALLISON M JOHNSON whose telephone number is (703)756-1396. The examiner can normally be reached Monday-Friday 9am-5pm.
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/ALLISON MARIE JOHNSON/Examiner, Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638