DETAILED ACTION
Election/Restrictions
Applicant’s election without traverse of Group I, Formula II, T is an antibody that specifically binds a cell surface antigen on a cancer cell, linker is a linear protease cleavable peptide linker 17 amino acids in length that contains a carboxytetramethylrodamine fluorophore that form the HES homodimer wherein the linker is cleavable by MMP14, oligo is an antisense oligonucleotide of 21 nucleotides in length that comprises phosphorothioate internucleoside linkages and is conjugated to a N-ethyl-N’-[5-(N”-succinimidyloxycarbonyl)pentyl] indocarbocyanine chloride fluorophore, HES contains 4 HES corresponding to 2 pairs of homo dimer HES wherein one pair is formed from fluorophore in linker above and the other pair is formed from the fluorophore in the oligo above in the reply filed on November 19 2025 is acknowledged.
Claims 4, 6, 13, 20, 25, 30, 39, 46, 53, 58, 66- 67, 76, 92, 94, 104, 108, 110, 120, 124, 126, 138, 147 and 158 are pending in the application. Claims 92, 94, 104, 108, 110, 120, 124, 126, 138, 147 and 158 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 November 19 2025. Accordingly, claims 4, 6, 13, 20, 25, 30, 39, 46, 53, 58, 66- 67 and 76 are being examined on the merits herein.
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 .
Priority
This application claims benefit of 63/221,606 ( 07/14/2021) as reflected in the filing receipt issued on November 25 2022.
Information Disclosure Statement
No IDS has been filed.
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 - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Specifically, the requirement is that “the size of the ASCII text file in bytes” not KB as currently written.
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 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.
Specification
The use of the terms Texas Red® (page 6; 41), BIACORE® (page 13; 35), PhiPhiLux® (page 27), Rhodamine GreenTM (page 5), LissamineTM (page 5), KynamroTM (page 134), RESPIGAMTM (page 145) , which are a trade name or a mark used in commerce, has been noted in this application. The 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.
Claim Objections
Claim 6 is objected to because of the following informalities: In part (d), there is a dash “-“ missing between 18 and 25 as well as 18 and 200. Appropriate correction is required.
Claim 6 is objected to because of the following informalities: in part (d), the “or” after “40,” and before “18” should be deleted. There is already an “or” present in the listing alternatives before the last choice. Appropriate correction is required.
Claim 13 is objected to because of the following informalities: The acronym “PNA” is not defined in the claims. When an acronym is used in a claim set, it should be defined the first time it appears in the claims. For the purposes of examination, the term “PNA” is interpreted to mean peptide nucleic acid. Appropriate correction is required.
Claim 13 is objected to because of the following informalities: in both parts (a) and (b) there is an extra dash “-“ between 2’ and deoxy; and 2’ and fluoro. Appropriate correction is required.
Claim 13 is objected to because of the following informalities: parts (a) and (b) have the same limitations. One needs to be deleted. Appropriate correction is required.
Claim 13 is objected to because of the following informalities: the abbreviations C-5 propyne and 5-methyl C need to be spelt out. When an acronym is used in a claim set, it should be defined the first time it appears in the claims. For the purposes of examination, the term “C-5 propyne” is interpreted to mean 5-propynyl-2’-deoxyuridine/cytosine and “5-methyl C” is interpreted to mean 5-methyl cytosine. Appropriate correction is required.
Claim 20 is objected to because of the following informalities: the claim must end in a period. Note: MPEP 608.01(m). Appropriate correction is required.
Claim 30 is objected to because of the following informalities: there is an extra comma “,” after 50 and before nucleotides in part (a) and (b). Appropriate correction is required.
Claim 46 is objected to because of the following informalities: in part (h) “comprises” should be “comprising”. Appropriate correction is required.
Claim 53 is objected to because of the following informalities: the abbreviations PSMA, BMP1, MMP, TTSP, DECC1, FAP, MT-SP1, TMPRSS and BACE. When an acronym is used in a claim set, it should be defined the first time it appears in the claims. Appropriate correction is required.
Claim 66 is objected to because of the following informalities: a comma “,” is missing between protein and a carbohydrate in line 3. Appropriate correction is required.
Claim 76 is objected to because of the following informalities: the abbreviations BEGFR, TIE1 and TIE2. When an acronym is used in a claim set, it should be defined the first time it appears in the claims. Appropriate correction is required.
Claim Rejections - 35 USC § 112-Indefinitness
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 4, 6, 13, 20, 25, 30, 39, 46, 53, 58, 66- 67 and 76 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.
Regarding claim 4, the phrase "such as" in the explanation of SP renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 6, the phrase "such as" in part (a) renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 6 as currently written is vague and indefinite. Part (b) of the claim indicates that a therapeutic oligonucleotide that contains 1,2 or 3 substitutions, deletions or insertions compared to the corresponding reverse complementary strand of the nucleic acid sequence. The comparison of the claimed therapeutic oligonucleotide is not clear. It is unclear what nucleic acid sequence is being references. There is insufficient antecedent basis for this limitation (the corresponding reverse complementary strand and the nucleic acid sequence) in the claim.
Claim 13 as currently written is vague and indefinite. Claim 13 as written includes the phrase in parts (a)-(c) “selected from…and”. Proper Markush language is “selected from the group consisting of” or “selected from…or”. The examiner suggests rewording the claim to include the Markush language. Note: MPEP 2111.03 and 2173.05(h). Markush language by nature is closed and makes it clear the species are in the alternative. However, the recitation of “selected from…and”, is not in the alternative. Therefore, the resulting claim is indefinite as it appears applicants are attempting to set up an alternative but the claims do not indicate as such. The claim recites “one or more modified” which indicates only one has to be present but the recitation “and” does not allow for alternatives to be selected.
Claim 20 as currently written is vague and indefinite. Claim 20 as written includes the phrase in part (d) “selected from…and”. Proper Markush language is “selected from the group consisting of” or “selected from…or”. The examiner suggests rewording the claim to include the Markush language. Note: MPEP 2111.03 and 2173.05(h). Markush language by nature is closed and makes it clear the species are in the alternative. However, the recitation of “selected from…and”, is not in the alternative. Therefore, the resulting claim is indefinite as it appears applicants are attempting to set up an alternative but the claims do not indicate as such. The claim recites “at least 1 fluorophore” which indicates only one has to be present but the recitation “and” does not allow for alternatives to be selected.
Claim 20 as currently written is vague and indefinite. In part (e) the claim recites “selected from…and” which doesn’t set forth the groups in the alternative. Additionally following the “and” there are two different indocarbocyanines listed. Based on the name it doesn’t not appear that these two compounds are the same. But there isn’t a conjunctions between the two species. Therefore, the claim is indefinite as the scope of the different fluorophores is unclear and they are not set forth in the alternative. Note: MPEP 2173.05(h).
Claim 25 as currently written is vague and indefinite. The claim utilizes the phrase “selected from…and” but this does not properly set forth a listing of alternatives. Note: MPEP 2173.05(h).
Claim 30 as currently written is vague and indefinite. The claim, in part (a) and (b) recites “contains 2 nucleic complementary nucleic acid strand”. The scope of this recitation is unclear. It is not clear what is complementary and what it is complementary to. The claim depends from claim 4 which merely recites a “therapeutic oligonucleotide”. Claim 30 does not clearly set forth the metes and bounds for the particular therapeutic nucleotide claimed.
Claim 30 recites the limitation "the RNA" in part (d) and (f). There is insufficient antecedent basis for this limitation in the claim. Neither claim 30 nor claim 4 (the claim form which it depends) indicates hybridization and does not specify what RNA is being referred to in the recitation “the RNA”.
Claim 39 recites the limitation "the therapeutic antisense oligonucleotide" in lines 1-2. The claim depends from claim 4 and claim 4 merely recites to a therapeutic oligonucleotide. There is insufficient antecedent basis for this limitation in the claim.
Claim 53 recites the limitation "the protease" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 53 depends from claim 4. Claim 4 never refers to a protease. Therefore it is unclear what protease is referring to.
Regarding claim 53, the phrase "for example" (aka e.g.) renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The claim utilizes the “for example” language when referring to a metalloproteinase, a matrix metalloprotease, an elastase, a cysteine protease, a serine protease, an aspartase protease and an aspartic cathepsin.
Regarding claim 53, the phrase "such as" (in the for example portion of a serine protease) renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 58, the phrase "for example" (aka e.g.) renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The claim utilizes the “for example” language in part (a), part (e) and part (h).
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 66 recites the broad recitation a receptor ligand, and the claim also recites including Fc fusion proteins containing the same which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Regarding claim 67, the phrase "for example" (aka e.g.) renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 76, the phrase "such as" in part (a), (b), (c) and (e) renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 46 is included in the rejection as they depend on a rejected base claim and they do not clarify the issues.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
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 4, 6, 13, 20, 25, 30, 39, 46, 53, 58, 66- 67 and 76 are rejected under 35 U.S.C. 103 as being unpatentable over Packard et al. (USPGPUB No. 20190183918) in view of Moore et al. (USPGPUB No. 20150087810) as evidenced by Gonzalez-Molina et al. (Cells, 2019).
Applicant Claims
The instant application claims a conjugate comprising a targeting moiety conjugated to an oligonucleotide-HES complex, wherein the conjugate has the structure of formula (I) T-(L~-(Oligo-HES)x,)p (I) wherein: T is a targeting moiety that selectively binds a target of interest; L is a linker; Oligo-HES is an oligonucleotide complex containing a therapeutic oligonucleotide and an H-type excitonic structure (HES); nis0or1;xis i to 30, 1-20, 1-10, or 1-5; and p is i to 30, 1-20, 1-10, or 1-5; or the structure of formula (II) T-[ L~ - ((Oligo2- SP) m - Oligol-HES)s], (II) wherein: T is a targeting moiety that selectively binds a target of interest; L is a linker; SP is a linker, optionally wherein SP is 6 to 12 amino acid residue peptide or alkyl chain spacer such as a C6, C10, or C18, linear or branched alkyl; Oligol-HES is an oligonucleotide complex containing oligonucleotide 1 (Oligol) and an H- type excitonic structure (HES); Oligo2 is an oligonucleotide that may be the same or different from Oligo1;nis0or1;m is 0 or 1; s is 1 or 2; and u is 1, 2, 3, 4, or 5.
Optionally in claim 4 is interpreted as not being required. Therefore any linker would read on a SP linker.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Packard et al. is directed to systemic in vivo delivery of oligonucleotides. Claimed is a H-type excitonic structure(HES)-oligonucleotide containing a therapeutic oligonucleotide that specifically hybridizes to a nucleic acid in vivo and modulates the level of a protein encoded by or regulated by the nucleic acid after delivery (claim 1). The therapeutic oligonucleotide is form about 8 to about 750 nucleotides (claim 2) and can be single stranded (claim 3) or double stranded (claim 4). The HES-oligonucleotide comprises 2 or more fluorophores capable of forming one or more HES (paragraph 0039). The therapeutic oligonucleotide is a siRNA, shRNA, miRNA, a Dicer substrate, an aptamer, a decoy and an antisense (claim 6). Compositions comprising one or more HES-oligonucleotides is taught (claim 27). Oligonucleotide strand contained in the complexes of the invention are between 21-25 nucleotides in length and have 1, 2 or 3 nucleotide overhangs (paragraph 0075; 0078-0080). Exemplified is a sequence of 24 nucleic acids complementary to bet-actin and covalently labeled on opposites of the strand with the fluorophore (N-Ethyl-N′-[5-(N″-succinimidyloxycarbonyl)pentyl]-3,3,3′,3′,-tetramethyl-2,2′-indodicarbocyanine chloride) (example 1). Linking one or more HES to a single or multiple strands of oligonucleotides is taught (paragraph 0224). In some embodiments, the HES-oligonucleotide delivery system is combined with one or more oligonucleotide delivery systems to further facilitate HES-oligonucleotide complex delivery into a cell and/or targeted delivery of the oligonucleotide. Additionally systems include conjugates with peptides or targeting nucleic acid motifs. Particular embodiments a HES-oligonucleotide complex is conjugated with an aptamer, peptide or antibody (paragraph 0153). Treating proliferative disorders such as cancers including those with solid tumors such as melanoma, pancreatic and breast cancer is taught (paragraph 0302; 0308). The invention also encompasses a method of treating a disease or disorder characterized by the overexpression of a protein in a subject, comprising systemically administering to the subject an HES-oligonucleotide complex, containing an oligonucleotide which is targeted to nucleic acids comprising or encoding a small non-coding RNA that influences the increased production of the protein, wherein the oligonucleotide act to reduce the levels of the small non-coding RNA and/or interfere with its function in the subject. In some embodiments, the oligonucleotide comprises a sequence substantially complementary to the small-noncoding RNA wherein diseases include cancer (paragraph 0204). Fluorophores include carboxytetramethylrhodamine (paragraph 0063).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Packard et al. suggests a HES-oligo complex and that such a complex can be linked to a targeting motif such as an antibody, Packard et al. does not expressly teach linking the HES-oligo complex to an antibody with a peptide linker which includes a protease cleavage site. However this deficiency is cured by Moore et al. as evidenced by Gonzalez-Molina et al.
Moore et al. is directed to matrix metalloproteinase substrates and other cleavable moieties and methods of use thereof. Taught are amino acid sequences that include a cleavable moiety (CM) that is a substrate for at least one matrix metalloprotease. The CMs are useful in a variety of therapeutic and diagnostic indications (paragraph 0005). The CM is a substrate for at least one matrix including MMP14 (paragraph 0006; claim 24). Linking an antibody to the CM is taught (claim 31). Figures 1A and B show the combination of a cleavage moiety comprising the MMP14 substrate, the heavy and light chains of the anti-EGFR antibody to inhibit tumor growth (paragraph 0179). Cancer targeting antibodies are specifically taught (paragraph 0321-0322). Multi-specific activatable antibodies that are activatable in a cancer microenvironment and include an antibody is taught (paragraph 0324; 0437). The antibody binds a target (claim 26) wherein the CM is a substrate for a protease that is co-localized in a tissue with the target (claim 27). The working examples demonstrate that the CM, when displayed in a peptide display platform, exhibit a number of desirable cleavage characteristics when exposed to an MMP protease under specific conditions (paragraph 0187). The antibodies can be detectably labeled (paragraph 0453). The CM is used to link one or more agents to the antibody that binds a given target such that the CM is cleaved when exposed to the MMP and the agent is released from the AB (paragraph 0009; 0261; 0269). The CM is a substrate for at least one MMP and comprises a polypeptide having a length less than 50 amino acids (paragraph 0023). The detectable label is position on a portion of the activatable antibody that is released following cleavage of the CM (paragraph 0464). Detectable labels include a fluorescent label such as rhodamine (paragraph 0057; 0309).
As evidenced by Gonzalez-Molina et al., MMP14 is up-regulated in several types of cancer, promoting angiogenesis, inflammation, cancer cell invasion and metastasis. MMP14 overexpression induces mammary gland adenocarcinoma formation and pancreatic cancer development. Mouse models of epithelial cancers have also identified MMP14 expression, particular in tumor-associated cells of the TME, to be involved in cancer progression (page 2, last paragraph).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Packard et al. and Moore et al. and conjugate the oligo-HES complexes of Packard et al. via a linker to an antibody. One skilled in the art would have been motivated to do this conjugation in order to target a particular cell/tissue as suggested by Moore et al. Since Packard et al. teaches that in some embodiments a HES-oligonucleotide complex is conjugated with an antibody there is a reasonable expectation of success.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Packard et al. and Moore et al. and utilize a MMP14 cleavable linker with a detectable fluorophore when conjugating the oligo-HES to the antibody. One skilled in the art would have been motivated to utilize a MMP14 cleavable linker when desiring the cleavage to occur in cancerous tissues where MMP14 is upregulated as suggested by Moore et al. Since as evidenced by Gonzalez-Molina et al., MMP14 is up-regulated in several types of cancer, there is a reasonable expectation of success. One skilled in the art would have been motivated to include detectable fluorophores in the linker such that fluorophores can be utilized to indicate that cleavage has occurred. Packard et al. suggests that 4 or more HES can be utilized and they can be the same or different (paragraph 0040) and that disruption in the HES can be used to identify and/or quantitate the presence of a nucleic acid of interest (paragraph 0009). This suggests using the fluorescence for identification. The use of different fluorophores along the molecule allows for identification of different aspects, specifically cleavage as well as presence of a nucleic acid. Regarding the fluorophore, Moore et al. teaches it can be rhodamine and Packard et al. teaches fluorophores include carboxytetramethylrhodamine. Therefore, it would have been obvious to one of ordinary skill in the art to utilize any of the specifically taught rhodamine fluorophores in order to allow for detection of the cleavage with a reasonable expectation of success.
Regarding the claimed structure (claim 4); as elected the structure is T-[L1-Oligo1-HES)]2. As set forth above Packard et al. suggests that the oligo-HES can be conjugated to an antibody and treating cancer. Moore et al. teaches antibodies which bind to cancer cells. This reads on the instantly claimed T. Moore et al. teaches a linker which can be cleaved in the presence of a MMP, specifically taught is MMP14, and this can contain a detectable fluorophore. As taught by Moore et al. the length of the linker is less than 50 amino acids which overlaps the elected length. This reads on L. Packard et al. teaches Oligo-HES and specifically teaches the oligo is therapeutic and exemplifies HES of (N-Ethyl-N′-[5-(N″-succinimidyloxycarbonyl)pentyl]-3,3,3′,3′,-tetramethyl-2,2′-indodicarbocyanine chloride) which is a (N-Ethyl-N′-[5-(N″-succinimidyloxycarbonyl)pentyl] -indocarbocyanine chloride. There can be 2 fluorophores to each oligonucleotide. The oligonucleotide is a therapeutic nucleotide which is 21-25 nucleotides in length and can be antisense for treating cancer reading on Oligo-HES. Packard et al. suggests the use of one or more HES-oligonucleotides. Thus the combination of Packard et al. and Moore et al. would suggest more than one linker-oligo-HES attached to the antibody. Such that upon the exposure to MMP14, the antibody and oligo-HES are cleaved releasing not only the antibody and fluorophore to indicate cleavage but the therapeutic oligo-HES complex. 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). Note MPEP 2144.05.
Regarding claim 6, Packard et al. at least teaches (a), (c) and (e) in claims 1-4.
Regarding claim 13, Packard et al. teaches all the same limitations in claims 20-24. Packard et al. also teaches that the complexes include at least one phosphorothioate internucleoside and specifically teaches that all of the linkages can be phosphorothioates (paragraph 0085).
Regarding claim 20, Packard et al. at least teaches (b), (d) and (e) in paragraph 0039 and examples.
Regarding claim 25, Packard et al. teaches the same in claim 6.
Regarding claim 30, Packard et al. teaches at least (a), (c), (d), (e), (f) and (g) in claims 2, 7-10 and paragraph 0075; 0078-0080.
Regarding claim 39, Packard et al. teaches the same limitations in claim 13.
Regarding claim 46 and 53, as set forth above, Moore et al. teaches a linker which comprises an amino acid that is a substrate for at least one protease and is cleavable wherein the protease is MMP14.
Regarding claim 58, as set forth above Moore et al. teaches a detectable fluorophore which can be rhodamine and Packard et al. teaches carboxytetramethylrhodamine are fluorophores reading on (e).
Regarding claim 66-67 and 76, as set forth above conjugation to an antibody is taught. The antibody targeting a cancer cell is taught by Moore et al.
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.
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Claims 4, 6, 13, 20, 25, 30, 39, 46, 53, 58, 66- 67 and 76 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-35 of U.S. Patent No. 7541143 in view of Packard et al. and Moore et al. as evidenced by Gonzalez-Molina et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant application claims a conjugate comprising a targeting moiety conjugated to an oligonucleotide-HES complex, wherein the conjugate has the structure of formula (I) T-(L~-(Oligo-HES)x,)p (I) wherein: T is a targeting moiety that selectively binds a target of interest; L is a linker; Oligo-HES is an oligonucleotide complex containing a therapeutic oligonucleotide and an H-type excitonic structure (HES); nis0or1;xis i to 30, 1-20, 1-10, or 1-5; and p is i to 30, 1-20, 1-10, or 1-5; or the structure of formula (II) T-[ L~ - ((Oligo2- SP) m - Oligol-HES)s], (II) wherein: T is a targeting moiety that selectively binds a target of interest; L is a linker; SP is a linker, optionally wherein SP is 6 to 12 amino acid residue peptide or alkyl chain spacer such as a C6, C10, or C18, linear or branched alkyl; Oligol-HES is an oligonucleotide complex containing oligonucleotide 1 (Oligol) and an H- type excitonic structure (HES); Oligo2 is an oligonucleotide that may be the same or different from Oligo1;nis0or1;m is 0 or 1; s is 1 or 2; and u is 1, 2, 3, 4, or 5.
Patent ‘143 claims a fluorogenic composition comprising a nucleic acid backbone joining two fluorophores of the same species wherein said nucleic acid backbone ranges in length from about 10 nucleotides to about 50 nucleotides and whereby said form an H-dimer resulting in quenching of the fluorescence of said fluorophores (claim 1) reading on a Oligo-HES complex. Fluorophores are selected from the group consisting of carboxytetramethylrhodamine, carboxyrhodamine-X, carboxyrhodamine 110, diethylaminocoumarin, and carbocyanine dyes (claim 13).
While Patent ‘143 claims an oligo-HES, Patent ‘143 does not expressly claim the instantly elected HES or that the oligo-HES is conjugated to an antibody via a peptide linker. However, these deficiencies are cured by Packard et al. and Moore et al. as evidenced by Gonzalez-Molina et al.
Packard et al. is directed to systemic in vivo delivery of oligonucleotides. Claimed is a H-type excitonic structure(HES)-oligonucleotide containing a therapeutic oligonucleotide that specifically hybridizes to a nucleic acid in vivo and modulates the level of a protein encoded by or regulated by the nucleic acid after delivery (claim 1). The therapeutic oligonucleotide is form about 8 to about 750 nucleotides (claim 2) and can be single stranded (claim 3) or double stranded (claim 4). The HES-oligonucleotide comprises 2 or more fluorophores capable of forming one or more HES (paragraph 0039). The therapeutic oligonucleotide is a siRNA, shRNA, miRNA, a Dicer substrate, an aptamer, a decoy and an antisense (claim 6). Compositions comprising one or more HES-oligonucleotides is taught (claim 27). Oligonucleotide strand contained in the complexes of the invention are between 21-25 nucleotides in length and have 1, 2 or 3 nucleotide overhangs (paragraph 0075; 0078-0080). Exemplified is a sequence of 24 nucleic acids complementary to bet-actin and covalently labeled on opposites of the strand with the fluorophore (N-Ethyl-N′-[5-(N″-succinimidyloxycarbonyl)pentyl]-3,3,3′,3′,-tetramethyl-2,2′-indodicarbocyanine chloride) (example 1). Linking one or more HES to a single or multiple strands of oligonucleotides is taught (paragraph 0224). In some embodiments, the HES-oligonucleotide delivery system is combined with one or more oligonucleotide delivery systems to further facilitate HES-oligonucleotide complex delivery into a cell and/or targeted delivery of the oligonucleotide. Additionally systems include conjugates with peptides or targeting nucleic acid motifs. Particular embodiments a HES-oligonucleotide complex is conjugated with an aptamer, peptide or antibody (paragraph 0153). Treating proliferative disorders such as cancers including those with solid tumors such as melanoma, pancreatic and breast cancer is taught (paragraph 0302; 0308). The invention also encompasses a method of treating a disease or disorder characterized by the overexpression of a protein in a subject, comprising systemically administering to the subject an HES-oligonucleotide complex, containing an oligonucleotide which is targeted to nucleic acids comprising or encoding a small non-coding RNA that influences the increased production of the protein, wherein the oligonucleotide act to reduce the levels of the small non-coding RNA and/or interfere with its function in the subject. In some embodiments, the oligonucleotide comprises a sequence substantially complementary to the small-noncoding RNA wherein diseases include cancer (paragraph 0204). Fluorophores include carboxytetramethylrhodamine (paragraph 0063).
Moore et al. is directed to matrix metalloproteinase substrates and other cleavable moieties and methods of use thereof. Taught are amino acid sequences that include a cleavable moiety (CM) that is a substrate for at least one matrix metalloprotease. The CMs are useful in a variety of therapeutic and diagnostic indications (paragraph 0005). The CM is a substrate for at least one matrix including MMP14 (paragraph 0006; claim 24). Linking an antibody to the CM is taught (claim 31). Figures 1A and B show the combination of a cleavage moiety comprising the MMP14 substrate, the heavy and light chains of the antiEGFR antibody to inhibit tumor growth (paragraph 0179). Cancer targeting antibodies are specifically taught (paragraph 0321-0322). Multispecific activatable antibodies that are activatable in a cancer microenvironment and include an antibody is taught (paragraph 0324; 0437). The antibody binds a target (claim 26) wherein the CM is a substrate for a protease that is co-localized in a tissue with the target (claim 27). The working examples demonstrate that the CM, when displayed in a peptide display platform, exhibit a number of desirable cleavage characteristics when exposed to an MMP protease under specific conditions (paragraph 0187). The antibodies can be detectably labeled (paragraph 0453). The CM is used to link one or more agents to the antibody that binds a given target such that the CM is cleaved when exposed to the MMP and the agent is released from the AB (paragraph 0009; 0261; 0269). The CM is a substrate for at least one MMP and comprises a polypeptide having a length less than 50 amino acids (paragraph 0023). The detectable label is position on a portion of the activatable antibody that is released following cleavage of the CM (paragraph 0464). Detectable labels include a fluorescent label such as rhodamine (paragraph 0057; 0309).
As evidenced by Gonzalez-Molina et al., MMP14 is up-regulated in several types of cancer, promoting angiogenesis, inflammation, cancer cell invasion and metastasis. MMP14 overexpression induces mammary gland adenocarcinoma formation and pancreatic cancer development. Mouse models of epithelial cancers have also identified MMP14 expression, particular in tumor-associated cells of the TME, to be involved in cancer progression (page 2, last paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘143, Packard et al. and Moore et al. and conjugate the oligo-HES complexes of Patent ‘143 via linker to an antibody. One skilled in the art would have been motivated to do this conjugation in order to target a particular cell/tissue as suggested by Moore et al. Since Packard et al. teaches that in some embodiments a HES-oligonucleotide complex is conjugated with an antibody there is a reasonable expectation of success as Packard et al. teach similar oligo-HES complexes as Patent ‘143.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘143, Packard et al. and Moore et al. and utilize a MMP14 cleavable linker with a detectable fluorophore when conjugating the oligo-HES to the antibody. One skilled in the art would have been motivated to utilize a MMP14 cleavable linker when desiring the cleavage to occur in cancerous tissues where MMP14 is upregulated as suggested by Moore et al. Since as evidenced by Gonzalez-Molina et al., MMP14 is up-regulated in several types of cancer, there is a reasonable expectation of success. One skilled in the art would have been motivated to include detectable fluorophores in the linker such that fluorophores can be utilized to indicate that cleavage has occurred. Packard et al. suggests that 4 or more HES can be utilized and they can be the same or different (paragraph 0040) and that disruption in the HES can be used to identify and/or quantitate the presence of a nucleic acid of interest (paragraph 0009). This suggests using the fluorescence for identification. The use of different fluorophores along the molecule allows for identification of different aspects, specifically cleavage as well as presence of a nucleic acid. Regarding the fluorophore, Moore et al. teaches it can be rhodamine and Packard et al. teaches fluorophores include carboxytetramethylrhodamine. Therefore, it would have been obvious to one of ordinary skill in the art to utilize any of the specifically taught rhodamine fluorophores in order to allow for detection of the cleavage with a reasonable expectation of success.
Regarding the claimed structure (claim 4); as elected the structure is T-[L1-Oligo1-HES)]2. As set forth above Packard et al. suggests that the oligo-HES can be conjugated to an antibody and treating cancer. Moore et al. teaches antibodies which bind to cancer cells. This reads on the instantly claimed T. Moore et al. teaches a linker which can be cleaved in the presence of a MMP, specifically taught is MMP14, and this can contain a detectable fluorophore. As taught by Moore et al. the length of the linker is less than 50 amino acids which overlaps the elected length. This reads on L. Packard et al. and Patent ‘143 teaches Oligo-HES and Packard et al. specifically teaches the oligo is therapeutic and exemplifies HES of (N-Ethyl-N′-[5-(N″-succinimidyloxycarbonyl)pentyl]-3,3,3′,3′,-tetramethyl-2,2′-indodicarbocyanine chloride) which is a (N-Ethyl-N′-[5-(N″-succinimidyloxycarbonyl)pentyl] -indocarbocyanine chloride. There can be 2 fluorophores to each oligonucleotide as claimed by Patent ‘143. The oligonucleotide is a therapeutic nucleotide which is 21-25 nucleotides in length and can be antisense for treating cancer as taught by Packard et al. and Patent ‘143 claims an overlapping range reading on Oligo-HES. Packard et al. suggests the use of one or more HES-oligonucleotides. Thus the combination of Packard et al. and Moore et al. would suggest more than one linker-oligo-HES attached to the antibody. Such that upon the exposure to MMP14, the antibody and oligo-HES are cleaved releasing not only the antibody and fluorophore to indicate cleavage but the therapeutic oligo-HES complex. 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). Note MPEP 2144.05.
Regarding claim 6, Packard et al. at least teaches (a), (c) and (e) in claims 1-4.
Regarding claim 13, Packard et al. teaches all the same limitations in claims 20-24.
Regarding claim 20, Packard et al. at least teaches (b), (d) and (e) in paragraph 0039 and examples.
Regarding claim 25, Packard et al. teaches the same in claim 6.
Regarding claim 30, Packard et al. teaches at least (a), (c), (d), (e), (f) and (g) in claims 2, 7-10 and paragraph 0075; 0078-0080.
Regarding claim 39, Packard et al. teaches the same limitations in claim 13.
Regarding claim 46 and 53, as set forth above, Moore et al. teaches a linker which comprises an amino acid that is a substrate for at least one protease and is cleavable wherein the protease is MMP14.
Regarding claim 58, as set forth above Moore et al. teaches a detectable fluorophore which can be rhodamine and Packard et al. teaches carboxytetramethylrhodamine are fluorophores reading on (e).
Regarding claim 66-67 and 76, as set forth above conjugation to an antibody is taught. The antibody targeting a cancer cell is taught by Moore et al.
Claims 4, 6, 13, 20, 25, 30, 39, 46, 53, 58, 66- 67 and 76 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 10557136 in view of Packard et al. and Moore et al. as evidenced by Gonzalez-Molina et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant claims are set forth above.
Patent ‘136 claims a method for modulating a target nucleic acid or protein in a subject, said method comprising administering to the subject an effective amount of an H-type excitonic structure (HES)-oligonucleotide containing a therapeutic oligonucleotide that specifically hybridizes to a target nucleic acid sequence in vivo and thereby modulates the level of a protein encoded or regulated by the nucleic acid (claim 1) reading on the instantly claimed oligo-HES. The therapeutic oligonucleotide can be an antisense of 18-25 nucleotides in length.
While Patent ‘136 claims an oligo-HES, Patent ‘136 does not expressly claim the instantly claimed fluorophores or linking the oligo-HES to an antibody via linker. However, these deficiencies are cured by Packard et al. and Moore et al. as evidenced by Gonzalez-Molina et al.
The teachings of Packard et al., Moore et al. and Gonzalez-Molina et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘136, Packard et al. and Moore et al. and conjugate the oligo-HES complexes of Patent ‘136 via linker to an antibody. One skilled in the art would have been motivated to do this conjugation in order to target a particular cell/tissue as suggested by Moore et al. Since Packard et al. teaches that in some embodiments a HES-oligonucleotide complex is conjugated with an antibody there is a reasonable expectation of success as Packard et al. teach similar oligo-HES complexes as Patent ‘136.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘136, Packard et al. and Moore et al. and utilize a MMP14 cleavable linker with a detectable fluorophore when conjugating the oligo-HES to the antibody. One skilled in the art would have been motivated to utilize a MMP14 cleavable linker when desiring the cleavage to occur in cancerous tissues where MMP14 is upregulated as suggested by Moore et al. Since as evidenced by Gonzalez-Molina et al., MMP14 is up-regulated in several types of cancer, there is a reasonable expectation of success. One skilled in the art would have been motivated to include detectable fluorophores in the linker such that fluorophores can be utilized to indicate that cleavage has occurred. Regarding the fluorophore, Moore et al. teaches it can be rhodamine and Packard et al. teaches fluorophores include carboxytetramethylrhodamine. Therefore, it would have been obvious to one of ordinary skill in the art to utilize any of the specifically taught rhodamine fluorophores in order to allow for detection of the cleavage with a reasonable expectation of success.
Regarding the claimed structure (claim 4); as elected the structure is T-[L1-Oligo1-HES)]2. As set forth above Packard et al. suggests that the oligo-HES can be conjugated to an antibody and treating cancer. Moore et al. teaches antibodies which bind to cancer cells. This reads on the instantly claimed T. Moore et al. teaches a linker which can be cleaved in the presence of a MMP, specifically taught is MMP14, and this can contain a detectable fluorophore. As taught by Moore et al. the length of the linker is less than 50 amino acids which overlaps the elected length. This reads on L. Packard et al. and Patent ‘136 teaches Oligo-HES and Packard et al. specifically teaches the oligo is therapeutic and exemplifies HES of (N-Ethyl-N′-[5-(N″-succinimidyloxycarbonyl)pentyl]-3,3,3′,3′,-tetramethyl-2,2′-indodicarbocyanine chloride) which is a (N-Ethyl-N′-[5-(N″-succinimidyloxycarbonyl)pentyl] -indocarbocyanine chloride. There can be 2 fluorophores to each oligonucleotide as claimed by Patent ‘136. The oligonucleotide is a therapeutic nucleotide which is 21-25 nucleotides in length and can be antisense for treating cancer as taught by Packard et al. and Patent ‘136 claims an overlapping range reading on Oligo-HES. Packard et al. suggests the use of one or more HES-oligonucleotides. Thus the combination of Packard et al. and Moore et al. would suggest more than one linker-oligo-HES attached to the antibody. Such that upon the exposure to MMP14, the antibody and oligo-HES are cleaved releasing not only the antibody and fluorophore to indicate cleavage but the therapeutic oligo-HES complex. 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). Note MPEP 2144.05.
Regarding claim 6, Patent ‘136 at least claims (a), (c) and (e) in claims 1, 6-9.
Regarding claim 13, Patent ‘136 claims all the same limitations in claims 10-11.
Regarding claim 20, Packard et al. at least teaches (b), (d) and (e) in paragraph 0039 and examples.
Regarding claim 25, Patent ‘136 claims the same in claim 13.
Regarding claim 30, Packard et al. teaches at least (a), (c), (d), (e), (f) and (g) in claims 2, 7-10 and paragraph 0075; 0078-0080.
Regarding claim 39, Packard et al. teaches the same limitations in claim 13.
Regarding claim 46 and 53, as set forth above, Moore et al. teaches a linker which comprises an amino acid that is a substrate for at least one protease and is cleavable wherein the protease is MMP14.
Regarding claim 58, as set forth above Moore et al. teaches a detectable fluorophore which can be rhodamine and Packard et al. teaches carboxytetramethylrhodamine are fluorophores reading on (e).
Regarding claim 66-67 and 76, as set forth above conjugation to an antibody is taught. The antibody targeting a cancer cell is taught by Moore et al.
Claims 4, 6, 13, 20, 25, 30, 39, 46, 53, 58, 66- 67 and 76 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11261443 in view of Packard et al. and Moore et al. as evidenced by Gonzalez-Molina et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant claims are set forth above.
Patent ‘443 claims a composition for delivering a therapeutic oligonucleotide to a subject comprising a HES-oligonucleotide containing a therapeutic oligonucleotide that specifically hybridizes to a nucleic acid sequence in a cell (claim 1).
While Patent ‘443 claims an oligo-HES, Patent ‘443 does not expressly claim the instantly claimed fluorophores or linking the oligo-HES to an antibody via linker. However, these deficiencies are cured by Packard et al. and Moore et al. as evidenced by Gonzalez-Molina et al.
The teachings of Packard et al., Moore et al. and Gonzalez-Molina et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘443, Packard et al. and Moore et al. and conjugate the oligo-HES complexes of Patent ‘443 via linker to an antibody. One skilled in the art would have been motivated to do this conjugation in order to target a particular cell/tissue as suggested by Moore et al. Since Packard et al. teaches that in some embodiments a HES-oligonucleotide complex is conjugated with an antibody there is a reasonable expectation of success as Packard et al. teach similar oligo-HES complexes as Patent ‘443.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘443, Packard et al. and Moore et al. and utilize a MMP14 cleavable linker with a detectable fluorophore when conjugating the oligo-HES to the antibody. One skilled in the art would have been motivated to utilize a MMP14 cleavable linker when desiring the cleavage to occur in cancerous tissues where MMP14 is upregulated as suggested by Moore et al. Since as evidenced by Gonzalez-Molina et al., MMP14 is up-regulated in several types of cancer, there is a reasonable expectation of success. One skilled in the art would have been motivated to include detectable fluorophores in the linker such that fluorophores can be utilized to indicate that cleavage has occurred. Regarding the fluorophore, Moore et al. teaches it can be rhodamine and Packard et al. teaches fluorophores include carboxytetramethylrhodamine. Therefore, it would have been obvious to one of ordinary skill in the art to utilize any of the specifically taught rhodamine fluorophores in order to allow for detection of the cleavage with a reasonable expectation of success.
Regarding the claimed structure (claim 4); as elected the structure is T-[L1-Oligo1-HES)]2. As set forth above Packard et al. suggests that the oligo-HES can be conjugated to an antibody and treating cancer. Moore et al. teaches antibodies which bind to cancer cells. This reads on the instantly claimed T. Moore et al. teaches a linker which can be cleaved in the presence of a MMP, specifically taught is MMP14, and this can contain a detectable fluorophore. As taught by Moore et al. the length of the linker is less than 50 amino acids which overlaps the elected length. This reads on L. Packard et al. and Patent ‘136 teaches Oligo-HES and Packard et al. specifically teaches the oligo is therapeutic and exemplifies HES of (N-Ethyl-N′-[5-(N″-succinimidyloxycarbonyl)pentyl]-3,3,3′,3′,-tetramethyl-2,2′-indodicarbocyanine chloride) which is a (N-Ethyl-N′-[5-(N″-succinimidyloxycarbonyl)pentyl] -indocarbocyanine chloride. The oligonucleotide is a therapeutic nucleotide which is 21-25 nucleotides in length and can be antisense for treating cancer as taught by Packard et al. and Patent ‘443 claims an overlapping range reading on Oligo-HES. Packard et al. suggests the use of one or more HES-oligonucleotides. Thus the combination of Packard et al. and Moore et al. would suggest more than one linker-oligo-HES attached to the antibody. Such that upon the exposure to MMP14, the antibody and oligo-HES are cleaved releasing not only the antibody and fluorophore to indicate cleavage but the therapeutic oligo-HES complex. 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). Note MPEP 2144.05.
Regarding claim 6, Patent ‘443 claims the same in claims 1-3.
Regarding claim 13, Patent ‘443 claims the same in claims 10-11.
Regarding claim 20, Patent ‘443 claims the same in claim 4 and Packard et al. at least teaches (b), (d) and (e) in paragraph 0039 and examples.
Regarding claim 25, Patent ‘443 claims the same in claim 5.
Regarding claim 30, Patent ‘443 claims the same in claim 7 and Packard et al. teaches at least (a), (c), (d), (e), (f) and (g) in claims 2, 7-10 and paragraph 0075; 0078-0080.
Regarding claim 39, Patent ‘443 claims the same in claim 14 and Packard et al. teaches the same limitations in claim 13.
Regarding claim 46 and 53, as set forth above, Moore et al. teaches a linker which comprises an amino acid that is a substrate for at least one protease and is cleavable wherein the protease is MMP14.
Regarding claim 58, as set forth above Moore et al. teaches a detectable fluorophore which can be rhodamine and Packard et al. teaches carboxytetramethylrhodamine are fluorophores reading on (e).
Regarding claim 66-67 and 76, as set forth above conjugation to an antibody is taught. The antibody targeting a cancer cell is taught by Moore et al.
Claims 4, 6, 13, 20, 25, 30, 39, 46, 53, 58, 66- 67 and 76 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 29-46 of copending Application No. 18421570 (USPGPUB No. 20240401040) in view of Packard et al. and Moore et al. as evidenced by Gonzalez-Molina et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
This is a provisional nonstatutory double patenting rejection.
The instant claims are set forth above.
Copending ‘570 claims a method for modulating the function or activity of a small-non-coding RNA in a subject, said method comprising administering to the subject an effective amount of an H-type excitonic structure (HES)-oligonucleotide comprising a therapeutic oligonucleotide that specifically hybridizes to a target small-non-coding RNA sequence in vivo and thereby reduces levels of the small-non-coding RNA and/or interferes with the function of the small-non-coding RNA in a cell (claim 1).
While Copending ‘570 claims an oligo-HES, Copending ‘570 does not expressly claim the instantly claimed fluorophores or linking the oligo-HES to an antibody via linker. However, these deficiencies are cured by Packard et al. and Moore et al. as evidenced by Gonzalez-Molina et al.
The teachings of Packard et al., Moore et al. and Gonzalez-Molina et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Copending ‘570 , Packard et al. and Moore et al. and conjugate the oligo-HES complexes of Copending ‘570 via linker to an antibody. One skilled in the art would have been motivated to do this conjugation in order to target a particular cell/tissue as suggested by Moore et al. Since Packard et al. teaches that in some embodiments a HES-oligonucleotide complex is conjugated with an antibody there is a reasonable expectation of success as Packard et al. teach similar oligo-HES complexes as Copending ‘570.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Copending ‘570 , Packard et al. and Moore et al. and utilize a MMP14 cleavable linker with a detectable fluorophore when conjugating the oilgo-HES to the antibody. One skilled in the art would have been motivated to utilize a MMP14 cleavable linker when desiring the cleavage to occur in cancerous tissues where MMP14 is upregulated as suggested by Moore et al. Since as evidenced by Gonzalez-Molina et al., MMP14 is up-regulated in several types of cancer, there is a reasonable expectation of success. One skilled in the art would have been motivated to include detectable fluorophores in the linker such that fluorophores can be utilized to indicate that cleavage has occurred. Regarding the fluorophore, Moore et al. teaches it can be rhodamine and Packard et al. teaches fluorophores include carboxytetramethylrhodamine. Therefore, it would have been obvious to one of ordinary skill in the art to utilize any of the specifically taught rhodamine fluorophores in order to allow for detection of the cleavage with a reasonable expectation of success.
Regarding the claimed structure (claim 4); as elected the structure is T-[L1-Oligo1-HES)]2. As set forth above Packard et al. suggests that the oligo-HES can be conjugated to an antibody and treating cancer. Moore et al. teaches antibodies which bind to cancer cells. This reads on the instantly claimed T. Moore et al. teaches a linker which can be cleaved in the presence of a MMP, specifically taught is MMP14, and this can contain a detectable fluorophore. As taught by Moore et al. the length of the linker is less than 50 amino acids which overlaps the elected length. This reads on L. Packard et al. and Patent ‘136 teaches Oligo-HES and Packard et al. specifically teaches the oligo is therapeutic and exemplifies HES of (N-Ethyl-N′-[5-(N″-succinimidyloxycarbonyl)pentyl]-3,3,3′,3′,-tetramethyl-2,2′-indodicarbocyanine chloride) which is a (N-Ethyl-N′-[5-(N″-succinimidyloxycarbonyl)pentyl] -indocarbocyanine chloride. The oligonucleotide is a therapeutic nucleotide which is 21-25 nucleotides in length and can be antisense for treating cancer as taught by Packard et al. and Copending ‘570 claims the same 21-25 nucleotides reading on Oligo-HES. Packard et al. suggests the use of one or more HES-oligonucleotides. Thus the combination of Packard et al. and Moore et al. would suggest more than one linker-oligo-HES attached to the antibody. Such that upon the exposure to MMP14, the antibody and oligo-HES are cleaved releasing not only the antibody and fluorophore to indicate cleavage but the therapeutic oligo-HES complex. 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). Note MPEP 2144.05.
Regarding claim 6, Copending ‘570 claims similar limitations 1, 34-35.
Regarding claim 13, Copending ‘570 claims all the same limitations in claims 36-37.
Regarding claim 20, Packard et al. at least teaches (b), (d) and (e) in paragraph 0039 and examples.
Regarding claim 25, copending ‘570 claim an antisense oligonucleotide (claim 32).
Regarding claim 30, Packard et al. teaches at least (a), (c), (d), (e), (f) and (g) in claims 2, 7-10 and paragraph 0075; 0078-0080.
Regarding claim 39, Packard et al. teaches the same limitations in claim 13.
Regarding claim 46 and 53, as set forth above, Moore et al. teaches a linker which comprises an amino acid that is a substrate for at least one protease and is cleavable wherein the protease is MMP14.
Regarding claim 58, as set forth above Moore et al. teaches a detectable fluorophore which can be rhodamine and Packard et al. teaches carboxytetramethylrhodamine are fluorophores reading on (e).
Regarding claim 66-67 and 76, as set forth above conjugation to an antibody is taught. The antibody targeting a cancer cell is taught by Moore et al.
Conclusion
The examiner has attempted to address all grammatical issues and indefinite language. The examiner requests Applicants help in reviewing the claims upon response.
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/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636